Optimized drug-eluting stent assembly

ABSTRACT

A stent assembly including a stent configured to be positioned in a body lumen, and a knitted stent jacket including an expansible mesh structure having a coverage area of less than 25%, having approximate aperture diameters greater than 20 micrometers, and surrounding an external surface of the stent and coaxially associated therewith, wherein the stent assembly elutes an amount of an active pharmaceutical agent.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.12/791,008, filed Jun. 1, 2010, now pending, which is a continuation ofU.S. patent application Ser. No. 12/513,851, filed May 6, 2009, nowabandoned, which is a national stage of PCT/IL2007/001442, filed Nov.21, 2007, which claims the benefit of U.S. Provisional Application No.60/860,486, filed Nov. 22, 2006, the disclosure of each of which ishereby incorporated herein by express reference thereto.

FIELD OF THE INVENTION

The present invention, in some embodiments thereof, relates to stentassemblies and, more particularly, but not exclusively, to stent jacketsdesigned to substantially reduce platelet aggregation, thus decreasing,even eliminating dependence on a platelet aggregation reducers.

BACKGROUND

Stents are now implanted in more than 70% of all percutaneous coronaryrevascularization procedures and routinely used in peripheral stenoticvasculature, for example stenotic carotid vessels and stenotic organvasculature.

A typical stent is typically formed with large, mesh-like, aperturesthat damage surrounding stenotic vessel tissue during stent expansion.During the first two days following stent placement a layer ofendothelial cells grows over the stent frame and the vessel, includingthe damaged tissue. The endothelial cells produce nitrites that preventemboli and associated sequelae in all but 0.8% of a stent-recipientpopulation.

While improving local circulation over the short term, stents do notremove the long-term danger of blockage in the very stenotic tissue thatthe stents treat as the damaged tissue is prone to form new scar tissuethat protrude through the stent mesh, leading to vessel blockage,referred to as restenosis.

Tubular jackets comprising a polymer having small apertures are oftendeployed with a stent to prevent restenosis through the larger stentapertures. While often preventing restenosis, jacketed stents cause asignificant increase in other life-threatening hazards. Groups of cellsin the endothelial tissue coating polymer stent jackets are oftenunstable, presenting a lifetime risk of developing clumps comprisingmultiple endothelial cells that freely float through the circulation.

Platelets are sticky, irregularly shaped, disk-like blood-born bodiesthat promote blood clotting and readily sense, aggregate around, andstick to, clumps of free-floating endothelial cells. An embolism ofaggregated platelets and endothelial cells presents a health threat thatcan form at any time following jacketed stent implantation; causing anestimated 2% of all jacketed stent recipients to eventually developnecrosis of vital organs and/or die.

Drug eluting jacketed stents, while reducing restenosis more thannon-eluting jacketed stents, may pose and even greater threat ofembolitic death than non-drug eluting stents.

(“Late Acute Thrombosis After Paclitaxel Eluting Stent Implantation”: F.Liistro; Heart; September 2001; Vol. 86, pages 262-264).

The tremendous and constant threat of emboli from jacketed stents hasresulted in lifetime administration of prophylactic activepharmaceutical ingredients (APIs) including Clopidogrel Bisulfate,herein Clopidogrel, a platelet aggregation-reducing API marketed asPlavix® by Sanofi-Aventis and Bristol-Myers Squibb.

Clopidogrel administration is not hazard-free. Clopidogrel is associatedwith many side effects, including ulcers, skin rashes, syncope(temporary loss of consciousness), myelotoxicity (bone marrow damage),and TTP (thrombotic thrombocytopenic purpura), characterized byspontaneous, formation of assemblyic thrombi that form emboli. The deathrate from TTP, even with immediate diagnosis and aggressive treatment,is approximately 30%.

(“Clopidogrel-Associated TTP: An Update of Pharmacovigilance EffortsConducted by Independent Researchers, Pharmaceutical Suppliers, and theFood and Drug Administration”; Zakarija, M D, et al; Stroke, February2004, pages 533-537).

Moreover, Clopidogrel may not prevent life-threatening emboli as currentdata shows that up to 30% of Clopidogrel recipients fail to developsufficiently reduced platelet aggregation.

(“Resistance To Clopidogrel: A Review Of The Evidence”: Nguyen MSc,Pharm, et al; Journal of the American College of Cardiology; 19 Apr.2005; Vol. 45, Issue 8, pages 1157-1164).

Moreover, conditions such as hereditary antithrombin deficiency (HD),are that not responsive to platelet aggregate prophylactic APIs such asClopidogrel. HD patients receiving Clopidogrel pose a unique at-riskpopulation as HD is often diagnosed only following a serious emboliticevent.

Further, people stricken with Auto Immune Deficiency Syndrome (AIDS) mayactually develop hemophilia as a result of Clopidogrel administration.Within the AIDS population, a sub-population particularly at risk fordeveloping hemophilia includes individuals having low CCR5 (CCR5 Delta32 homozygous genotype), which is resistant to infection with HIV-1.

Additionally those at risk for acquiring hemophilia appear to be in thepopulation group of immune-suppressed individuals, including geriatricsdiabetics and those in the early stages of an HIV infection.

(“Acquired Haemophilia May Be Associated With Clopidogrel” Montaser Hajet al; British Medical Journal August 2004; pages 329:323).

In addition to the health hazards affecting the above-noted populationgroups, there are significant risks to every jacketed stent recipientreceiving lifetime Clopidogrel.

To prevent excessive bleeding in conjunction with virtually any surgery,Clopidogrel administration must be ceased for a significant period oftime both pre-operatively and post-operatively. As a result, patientsand surgeons are presented with a Hobson's choice of ceasing Clopidogreladministration and risking death from emboli or continuing Clopidogreland risking embolism-free bleeding, hemorrhage and death.

In general, jacketed stents, while aiding in preventing restenosis, areassociated with many significant, as yet unsolved, problems that canresult in death.

There is thus a widely recognized need for a stent jacket that does notrequire the administration of a platelet aggregation reducing API and itwould be highly advantageous to have, a stent devoid of the abovelimitations.

SUMMARY OF THE INVENTION

The disclosure encompasses a stent assembly that includes a stentconfigured to be positioned in a body lumen, and a knitted stent jacketincluding an expansible mesh structure having a coverage area of lessthan 25%, having approximate aperture diameters greater than 20micrometers, and surrounding an external surface of the stent andcoaxially associated therewith, wherein the stent assembly elutes anamount of an active pharmaceutical agent. In one embodiment, the activepharmaceutical agent is eluted from the stent. In another embodiment,the active pharmaceutical agent is eluted from a coating disposed over aportion of the stent. In yet another embodiment, the activepharmaceutical agent is time-released according to a predeterminedtreatment schedule. In one embodiment, the treatment schedule covers aperiod of 8 hours to a plurality of months. In a different embodiment,the active pharmaceutical agent is eluted from the knitted stent jacket.In yet a further embodiment, the active pharmaceutical agent is elutedfrom a coating on the expansible mesh structure. In another embodiment,the coaxial association includes the knitted stent jacket being sewed,adhered, glued, folded, or sutured to the stent. In one preferredembodiment, the coaxial association is that the knitted stent jacket issutured to the stent.

In one embodiment, a proximal portion of the knitted stent jacket isattached to a proximal portion of the stent. In a preferred embodiment,a distal portion of the stent jacket is attached to a distal portion ofthe stent. In another preferred embodiment, the amount of activepharmaceutical agent eluted includes a therapeutically effective amount.In yet another embodiment, the active pharmaceutical agent is elutedfrom the stent, a coating on the stent, the knitted stent jacket, acoating on the knitted stent jacket, or any combination thereof. In yeta further embodiment, a second, different active pharmaceutical agent iseluted from the stent, a coating on the stent, the knitted stent jacket,a coating on the knitted stent jacket, or any combination thereof. Inyet another embodiment, the mesh structure is formed from a polymercomponent including one or more poly lactic-co-polyglycolic (“PLGA”),polycaprolactone (“PCL”), polygluconate, polylactic acid-polyethyleneoxide, poly(hydroxybutyrate), polyanhydride, poly-phosphoester,poly(amino acids), poly-L-lactide, poly-D-lactide, polyglycolide, orpoly(alpha-hydroxy acid) co-polymer(s), polyethylene terephthalate, orany combination thereof. In one preferred embodiment, the mesh structureincludes a single polymer fiber or a plurality of individual polymerfibers. In another preferred embodiment, the polymer is elastic,biocompatible, and hemocompatible. In another embodiment, the knittedstent jacket includes a mesh of knit fibers each having diameter fromapproximately 7 to 40 micrometers. In a different embodiment, theexpansible mesh structure includes a retracted state and a deployedstate, and further wherein the expansible mesh structure definesapertures having a minimum center dimension of 150 micrometers to 200micrometers in the deployed state. In one preferred embodiment, theexpansible mesh structure includes a retracted state and a deployedstate, and further wherein the expansible mesh structure definesapertures having a minimum center dimension of 150 micrometers to 180micrometers in the deployed state.

In one embodiment, the active pharmaceutical agent includes a liposome,a steroid, a statin, an anticoagulant, gemcitabine, zolimus orzotarolimus, sirolimus, taxol/paclitaxel, or a combination thereof. Inanother embodiment, the active pharmaceutical agent includes zolimus,sirolimus, taxol/paclitaxel, or a combination thereof. In a furtherembodiment, the active pharmaceutical agent includes ananti-proliferative agent, an antithrombotic agent, and antioxidant, agrowth factor inhibitor, a collagen inhibitor, a liposome, a steroid orcorticosteroid, a statin, endothelial cell seeds, a hydrogel containingendothelial cells, or a combination thereof. In one preferredembodiment, the anti-proliferative agent is present and includessirolimus, zolimus or zotarolimus, a taxane, tacrolimus, everolimus,vincritine, viblastine, a HMG-CoA reductase inhibitor, doxorubicin,colchicine, actinomycin D, mitomycin C, cycloporine, mycophenolic acid,triazolopyrimidine, or a combination thereof; wherein the antithromboticagent is present and includes heparin, a heparin-like dextranderivative, acid citrate dextrose, coumadin, warfarin, streptokinase,anistreplase, tissue plasminogen activator (tPA), urokinase, abciximab,or a combination thereof; wherein the growth factor inhibitor is presentand includes tranilast, angiopeptin, or a combination thereof; whereinthe steroid or corticosteroid is present and includes cortisone,prednisolone, or both; wherein the statin is present and includessimvastatin, lovastatin, or a combination thereof; or any combination ofthe foregoing.

In one embodiment, the stent assembly includes 1 microgram to 200micrograms of each pharmaceutical agent. In another embodiment, the meshof the knitted stent jacket includes 1 microgram to 200 micrograms ofeach pharmaceutical agent. In one specific embodiment, the stent has asurface that includes around 1 μg/mm² of taxol. In one embodiment, theactive pharmaceutical agent includes a limus drug at a concentration of10 μg/mm² to 80 μg/mm². In another embodiment, the active pharmaceuticalagent includes a limus drug at a concentration of 80 μg/mm² to 140μg/mm². In a further embodiment, the knitted stent jacket is uncoated.

In one preferred embodiment, the stent includes a metal alloy coatedwith a biodegradable polymer, biostable polymer, bioresorbable polymer,or a combination thereof. In another preferred embodiment, the stentincludes a biodegradable material. In one embodiment, the biodegradablematerial includes a polymer. In yet another embodiment, thebiodegradable material includes a metal alloy.

The disclosure also encompasses, in a second aspect, a stent assembly,including a stent configured to be positioned in a body lumen, whichstent includes a metal alloy coated with a bioresorbable polymer,biostable polymer, biodegradable polymer, or a combination thereof, anda knitted stent jacket including an expansible mesh structure having acoverage area of less than 25% and surrounding an external surface ofthe stent, where a distal and a proximal portion of the stent jacket isattached to a distal and proximal aspect of the stent, wherein the stentelutes a therapeutically effective amount of an active pharmaceuticalagent including zolimus or zotarolimus, sirolimus, taxol/paclitaxel, ora combination thereof. In one preferred embodiment, the mesh structureis formed from a polymer component including one or more polylactic-co-polyglycolic (“PLGA”), polycaprolactone (“PCL”),polygluconate, polylactic acid-polyethylene oxide,poly(hydroxybutyrate), polyanhydride, poly-phosphoester, poly(aminoacids), poly-L-lactide, poly-D-lactide, polyglycolide, orpoly(alpha-hydroxy acid) co-polymer(s), polyethylene terephthalate, orany combination thereof.

According to another aspect of the present invention there is provided amethod of stenting, comprising: implanting a stent assembly in a vesselof a subject, the stent assembly, including: a stent jacket, comprisingan expansible mesh structure, formed of fibers of a diameter betweenabout 7 micrometers and about 18 micrometers, the diameter having aproperty of forming a substantially stable layer of endothelial cells,covering the fibers, thus reducing platelet aggregation, and anexpansible stent, operatively associated with the stent jacket. Themethod further comprises administering to the subject an activepharmaceutical ingredient (API) comprising a platelet aggregationreducer for a shortened time period, not exceeding six months, theshortened time period being a consequence of the property.

In embodiments, the shortened time period does not exceed five months.

In embodiments, the shortened time period does not exceed four months.

In embodiments, the shortened time period does not exceed three months.

In embodiments, the shortened time period does not exceed two months.

In embodiments, the shortened time period does not exceed one month.

In embodiments, during the shortened time period, the subject displays areaction to the platelet aggregation reducer, and further includingeliminating the administration of the platelet aggregation reducer.

In embodiments, the reaction is selected from the group consisting ofulcers, skin rashes, syncope, myelotoxicity and thromboticthrombocytopenic purpura (TTP).

In embodiments, during the shortened time period, the subject displays acondition requiring eliminating administration of the plateletaggregation reducer, the condition from the group of conditionscomprising: unresponsiveness to a platelet aggregate reducing API, anantithrombin deficiency, hereditary antithrombin deficiency (HD), immunedepression, low CCR5 Delta 32 homozygous genotype (CCR5), acquiredhemophilia, Immune Deficiency Syndrome (AIDS), and HIV.

According to an aspect of the present invention there is provided amethod of stenting, comprising implanting a stent assembly in a vesselof a subject, the stent assembly, including a stent jacket, comprisingan expansible mesh structure, formed of fibers of a diameter betweenabout 7 micrometers and about 18 micrometers, the diameter having aproperty of forming a substantially stable layer of endothelial cells,covering the fibers, thus reducing platelet aggregation, and anexpansible stent, operatively associated with the stent jacket. Themethod further comprises eliminating drug administration to the subjectin consequence of the property.

In embodiments, the diameter is between about 10 micrometers and about15 micrometers.

In embodiments, the diameter is between about 11 micrometers and about14 micrometers.

In embodiments, the diameter is between about 12 micrometers and about13 micrometers.

In embodiments, the diameter is between about 12.5 micrometers. Inembodiments, the mesh is formed as a single knit. In embodiments, thefiber is formed from multiple filaments.

In embodiments, the expansible mesh structure comprises a retractedstate and a deployed state, and further wherein in the deployed state,the expansible mesh structure defines apertures, having a minimum centerdimension, which is greater than about 180 micrometers, thus minimizingoccurrences of a single endothelial cell adhering to more than onefiber, across one of the apertures, and reducing a chance of endothelialcells breaking free as a result of natural stent pulsation with bloodflow.

In embodiments, the minimum center dimension is greater than about 200micrometers.

In embodiments, the fibers are formed of a material, which encouragesstable adherence of endothelial cells to the fibers.

In embodiments, the material is selected from the group consisting of:stainless steel, nitinol, titanium, gold, a biostable polymer, and anatural polymer.

According to an aspect of the present invention there is provided amethod of stenting, comprising: implanting a stent assembly in a vesselof a subject, the stent assembly, including a stent jacket, comprisingan expansible mesh structure, having a retracted state and a deployedstate, and further wherein in the deployed state, the expansible meshstructure defines apertures, having a minimum center dimension, which isgreater than about 180 micrometers, thus minimizing occurrences of asingle endothelial cell adhering to more than one fiber, across one ofthe apertures, and reducing a chance of endothelial cells breaking freeas a result of natural stent pulsation with blood flow, and anexpansible stent, operatively associated with the stent jacket. Themethod further comprises administering to the subject an activepharmaceutical ingredient (API) comprising a platelet aggregationreducer for a shortened time period, not exceeding six months, theshortened time period being a consequence of the minimum centerdimension.

In embodiments, the shortened time period does not exceed five months.

In embodiments, the shortened time period does not exceed four months.

In embodiments, the shortened time period does not exceed three months.

In embodiments, the shortened time period does not exceed two months.

In embodiments, the shortened time period does not exceed one month.

In embodiments, during the shortened time period, the subject displays areaction to the platelet aggregation reducer, and further includingeliminating the administration of the platelet aggregation reducer.

In embodiments, the reaction is selected from the group consisting ofulcers, skin rashes, syncope, myelotoxicity and TTP.

In embodiments, during the shortened time period, the subject displays acondition requiring eliminating administration of the plateletaggregation reducer, the condition from the group of conditionscomprising: unresponsiveness to a platelet aggregate reducing API, anantithrombin deficiency, HD, immune depression, low CCR5, acquiredhemophilia, AIDS, HIV.

According to an aspect of the present invention there is provided amethod of stenting, comprising implanting a stent assembly in a vesselof a subject, the stent assembly, including a stent jacket, comprisingan expansible mesh structure, having a retracted state and a deployedstate, and further wherein in the deployed state, the expansible meshstructure defines apertures, having a minimum center dimension, which isgreater than about 180 micrometers, thus minimizing occurrences of asingle endothelial cell adhering to more than one fiber, across one ofthe apertures, and reducing a chance of endothelial cells breaking freeas a result of natural stent pulsation with blood flow, and anexpansible stent, operatively associated with the stent jacket. Themethod further comprises eliminating drug administration to the subject,in consequence of the minimum center dimension.

In embodiments, wherein the minimum center dimension is greater thanabout 200 micrometers.

In embodiments, wherein the expansible mesh structure is formed offibers of a diameter between about 7 micrometers and about 18micrometers, the diameter having a property of forming a substantiallystable layer of endothelial cells, covering the fibers, thus reducingplatelet aggregation.

In embodiments, the diameter is between about 10 micrometers and about15 micrometers.

In embodiments, the diameter is between about 11 micrometers and about14 micrometers.

In embodiments, the diameter is between about 12 micrometers and about13 micrometers.

In embodiments, the diameter is between about 12.5 micrometers.

In embodiments, the mesh is formed as from single fiber. In embodiments,the fibers are formed from multiple filaments.

In embodiments, the fibers are formed of a material, which encouragesstable adherence of endothelial cells to the fibers.

In embodiments, the material is selected from the group consisting of:stainless steel, nitinol, titanium, gold, a biostable polymer, and anatural polymer.

According to an aspect of the present invention there is provided astent assembly, comprising: a stent jacket, comprising an expansiblemesh structure, formed of fibers of a diameter between about 10micrometers and about 15 micrometers, the diameter having a property offorming a substantially stable layer of endothelial cells, covering thefibers, thus reducing platelet aggregation, and an expansible stent,operatively associated with the stent jacket.

In embodiments, the diameter is between about 11 micrometers and about14 micrometers.

In embodiments, the diameter is between about 12 micrometers and about13 micrometers.

In embodiments, the diameter is between about 12.5 micrometers.

In embodiments, the mesh is formed as a single knit. In embodiments, thefibers are formed from multiple filaments.

In embodiments, the expansible mesh structure comprises a retractedstate and a deployed state, and further wherein in the deployed state,the expansible mesh structure defines apertures, having a minimum centerdimension, which is greater than about 180 micrometers, thus minimizingoccurrences of a single endothelial cell adhering to more than onefiber, across one of the apertures, and reducing a chance of endothelialcells breaking free as a result of natural stent pulsation with bloodflow.

In embodiments, the minimum center dimension is greater than about 200micrometers.

In embodiments, the fibers are formed of a material, which encouragesstable adherence of endothelial cells to the fibers.

In embodiments, the material is selected from the group consisting of:stainless steel, nitinol, titanium, gold, a biostable polymer, and anatural polymer.

According to an aspect of the present invention there is provided astent assembly, comprising: a stent jacket, comprising an expansiblemesh structure, having a retracted state and a deployed state, andfurther wherein in the deployed state, the expansible mesh structuredefines apertures, having a minimum center dimension, which is greaterthan about 180 micrometers, thus minimizing occurrences of a singleendothelial cell adhering to more than one fiber, across one of theapertures, and reducing a chance of endothelial cells breaking free as aresult of natural stent pulsation with blood flow, and an expansiblestent, operatively associated with the stent jacket.

In embodiments, the minimum center dimension is greater than about 200micrometers.

In embodiments, the expansible mesh structure is formed of fibers of adiameter between about 7 micrometers and about 18 micrometers, thediameter having a property of forming a substantially stable layer ofendothelial cells, covering the fibers, thus reducing plateletaggregation.

In embodiments, the diameter is between about 10 micrometers and about15 micrometers.

In embodiments, the diameter is between about 11 micrometers and about14 micrometers.

In embodiments, the diameter is between about 12 micrometers and about13 micrometers.

In embodiments, the diameter is between about 12.5 micrometers. Inembodiments, the mesh is formed as a single knit. In embodiments, thefibers are formed from multiple filaments.

In embodiments, the fibers are formed of a material, which encouragesstable adherence of endothelial cells to the fibers.

In embodiments, the material is selected from the group consisting of:stainless steel, nitinol, titanium, gold, a biostable polymer, and anatural polymer.

Unless otherwise defined, all technical and/or scientific terms usedherein have the same meaning as commonly understood by one of ordinaryskill in the art to which the invention pertains. Although methods andmaterials similar or equivalent to those described herein can be used inthe practice or testing of embodiments of the invention, exemplarymethods and/or materials are described below. In case of conflict, thepatent specification, including definitions, will control. In addition,the materials, methods, and examples are illustrative only and are notintended to be necessarily limiting.

BRIEF DESCRIPTION OF THE DRAWINGS

Exemplary non-limiting embodiments of the invention are described in thefollowing description, read with reference to the figures attachedhereto. In the figures, identical and similar structures, elements orparts thereof that appear in more than one figure are generally labeledwith the same or similar references in the figures in which they appear.Dimensions of components and features shown in the figures are chosenprimarily for convenience and clarity of presentation and are notnecessarily to scale. The attached figures are:

FIG. 1 is a perspective view of an enhanced stent apparatus, in an open,non-crimped mode, in accordance with an exemplary embodiment of theinvention;

FIG. 2 is a cross-sectional side view of an enhanced stent apparatus, inaccordance with an exemplary embodiment of the invention;

FIG. 3 is an illustration of an enhanced stent apparatus in an open modein situ, in accordance with an exemplary embodiment of the invention;

FIG. 4 is a perspective view of an enhanced stent apparatus, withmultiple helical coils in an open mode, in accordance with an exemplaryembodiment of the invention;

FIG. 5 is a perspective view of an enhanced stent apparatus, in acrimped, closed mode, in accordance with an exemplary embodiment of theinvention;

FIG. 6A is a perspective view of a knitted porous structure enhancedstent apparatus in an open mode, in accordance with an exemplaryembodiment of the invention;

FIG. 6B is a detailed view of a knitted porous structure, in accordancewith an exemplary embodiment of the invention;

FIG. 7 is a perspective view of a braided porous structure enhancedstent apparatus, in accordance with an exemplary embodiment of theinvention;

FIG. 8 is a perspective view of an enhanced stent apparatus on anangioplasty balloon, in accordance with an exemplary embodiment of theinvention;

FIG. 9 is a perspective view of an enhanced stent apparatus, providedwith longitudinal non-stretchable wires, and horizontal stretchableelastomers in accordance with an exemplary embodiment of the invention;

FIG. 10 is a perspective view of an enhanced stent apparatus, whereinporous structure is longer than the support element, in accordance withan exemplary embodiment of the invention;

FIG. 11 is a perspective view of an enhanced stent apparatus, whereinporous structure is significantly greater in diameter than a crimpedsupport element, and is folded on itself for insertion into a lumen, inaccordance with an exemplary to embodiment of the invention;

FIG. 12 is a perspective view of a porous structure significantlygreater in diameter than an at least partially deflated balloon whereinthe porous structure is folded on itself for insertion into a lumen, inaccordance with an exemplary embodiment of the invention;

FIG. 13 illustrates the use of a funnel to reduce the diameter of atleast a porous structure, in accordance with an exemplary embodiment ofthe invention;

FIG. 14 illustrates using a stretchable rubber tube for manufacturing acompressed porous structure, in accordance with an exemplary embodimentof the invention;

FIG. 15 is a graph showing fiber thickness vs. percentage of porousstructure surface area that is structure, in accordance with anexemplary embodiment of the invention;

FIG. 16 is a detailed illustration of a threading method for securing aporous structure to a support element, in accordance with an exemplaryembodiment of the invention;

FIG. 17 is a detailed illustration of a knotting method for securing aporous structure to a support element, in accordance with an exemplaryembodiment of the invention;

FIG. 18 is a cross-section view of an enhanced stent apparatus showing aporous structure folding technique, in accordance with an exemplaryembodiment of the invention;

FIG. 19 is a schematic showing a method for manufacturing a porousstructure, in accordance with an exemplary embodiment of the invention;

FIG. 20A is an illustration of a typical aneurism;

FIG. 20B is an illustration of a prior art technique for treating ananeurism;

FIG. 20C is an illustration of a technique for treating an aneurism, inaccordance with an exemplary embodiment of the invention;

FIG. 21A is a cross-sectional view of a slip ring in a reduced profileconfiguration, in accordance with an exemplary embodiment of theinvention;

FIG. 21B is a cross-sectional view of a slip ring in a deployedconfiguration, in accordance with an exemplary embodiment of theinvention;

FIG. 22 is cross sectional view of a porous structure with anendothelium cell layer overgrowing it, in accordance with an exemplaryembodiment of the invention;

FIG. 23 is an illustration of a prior art situation in which a clump ofendothelial cells detaches from a stent strut;

FIGS. 24 a-24 d show deployment of a self-expanding stent, according toembodiments of the invention;

FIGS. 25-28 show in situ details of a typical stent jacket material inthe art, in situ; and

FIG. 29 shows a portion of the knitted stent jacket, according toembodiments of the invention;

FIG. 30 shows a plan view of the knitted stent jacket of FIG. 29,according to embodiments of the invention;

FIGS. 31-32 show details of the material comprising the knitted stentjacket of FIG. 29, according to embodiments of the invention; and

FIG. 33 shows in situ details of the material shown in FIGS. 8-9,according to embodiments of the invention.

DETAILED DESCRIPTION OF EXEMPLARY EMBODIMENTS

The instant application is divided into a number of labeled sectionswhich generally include, in order, descriptions of apparatuses (e.g.porous structures, stents, etc.), materials and methods formanufacturing the apparatuses, the usage of pharmaceuticals with theapparatuses and methods of using the apparatuses. It should beunderstood that the section headings are for clarity only, and are notintended to limit the subject matter described therein. Furthermore,some of the subject matter described in a particular section may belongin more than one section and therefore, some of the material couldoverlap between sections.

Introduction

Aspects of the present invention successfully address shortcomings ofthe prior art by providing a stent assembly having a low-bulk meshjacket designed to promote a stable layer of endothelial cells.

In accordance with some embodiments of the present invention, the meshcomprises a fiber having a low diameter that allows each endothelialcell to fully cover and overlap each fiber, thereby forming a layer ofendothelial cells that adhere to tissue on either side of the fiber. Thethus formed endothelial layer is substantially stable with asubstantially reduced tendency to break away and form emboli.

In accordance with some embodiments of the present invention, the meshfiber comprises material that encourages adherence of endothelial cells,thereby encouraging endothelial layer stability.

In accordance with some embodiments of the present invention, the meshis not secondarily processed for example with a chemical coating thatmay diminish endothelial adherence. Additionally, the absence ofchemical coatings serves to maintain low bulk fibers and fiberjunctions, where a first fiber passes over or under a secondfiber—another feature that contributes to endothelial layer stability.

In accordance with some embodiments of the present invention, each meshfiber is spaced a distance from a neighboring fiber thereby preventing asingle endothelial cell from adhering to more than one fiber, therebyreducing the chance that endothelial cells will break free of the stent,for example as a result of natural stent pulsation during blood flow.

In accordance with some embodiments of the present invention, the stentjacket optionally comprises a mesh that is knitted. In accordance withsome embodiments of the present invention, the stent jacket mesh isoptionally formed from a single fiber or a single group of fibers.

Overview of Enhanced Stent Apparatus

The present invention, in some embodiments thereof, relates to stentassemblies, as presented in PCT Patent Application PCT/IB2006/051874,the disclosure of which is hereby incorporated herein by expressreference thereto.

In an exemplary embodiment of the invention, an apparatus is providedwhich includes a porous structure and, optionally, an underlying supportelement, such as a stent (wherein underlying means the porous structureis between the support element and a lumen wall).

In some exemplary embodiments of the invention, an enhanced stentapparatus, including the porous structure and a stent, is used to treatstenosis and/or restenosis. In some exemplary embodiments of theinvention, the enhanced stent apparatus furnishes at least one of amultiplicity of benefits over a conventional arterial stent. Forexample, the enhanced stent apparatus is optionally used to preventplaque from getting into the blood stream to cause embolism, since theporous structure is made with small enough apertures (sizes indicatedbelow) to hold detached plaque in place. In an embodiment of theinvention, use of a porous structure replaces the use of an embolismprotection device during stent implantation. Optionally, the “umbrella”type embolism protection device is not used. Optionally, the porousstructure is used in conjunction with an embolism protection device forenhanced protection over the method of using an embolism protectiondevice during the implantation of a conventional arterial stent. In anembodiment of the invention, the enhanced stent apparatus delivers morecomprehensive pharmacological assistance to a treated area thanconventional stents. In some embodiments of the invention, the enhancedstent apparatus is optimized to encourage endothelial cell growth and/ormigration.

FIG. 1 shows a perspective view of an enhanced stent apparatus 100, inan exemplary embodiment of the invention. A support element 102 isdesigned and constructed to expand a blood vessel in a radial fashionfrom a central axis 106 of the enhanced stent apparatus 100. Optionally,support element 102 is tubular in shape. In some exemplary embodimentsof the invention, support element 102 is constructed of a flexible,biocompatible material. Optionally, support element 102 is constructedof stainless steel, nitinol, and/or cobalt chromium and/or other metalalloys (e.g. magnesium alloy). Optionally, support element 102 isconstructed of polymer either biostable or bioresorbable. In someexemplary embodiments of the invention, support element 102 is avascular stent, such as those made by Cordis®, Boston Scientific® and/orMedtronic®, for example.

In an exemplary embodiment of the invention, support element 102 iscovered by at least one porous structure 104. Optionally, supportelement 102 acts as a support structure for porous structure 104, forexample to provide radial support and or to maintain a desired shape ofporous structure 104. FIG. 2, shows a cross-sectional view of anenhanced stent apparatus. In this embodiment, support element 102supplies structural support to porous structure 104, which is located onthe exterior of support element 102.

In some exemplary embodiments of the invention, porous structure 104 islaid on the exterior of support element 102 and thereby overlaps gaps insupport element 102 (making the aperture sizes of the device as a wholesmaller, for example 150 microns), since conventional stent constructionusually results in multiple gaps in the structure of the stem, typicallyseveral millimeters. In other exemplary embodiments of the invention,porous structure 104 covers only a portion of support element 102. Forexample, only a portion of support element 102 is covered to avoidrestricting luminal flow to a branching vessel.

In some exemplary embodiments of the invention, porous structure 104extends past at least one end of support element 102. This can, forexample, better treat the inside surface of a blood vessel at an edge ofenhanced stent apparatus 100, where it is more likely to haverestenosis. In an exemplary embodiment of the invention, porousstructure 104 pads and/or treats trauma caused by the edge of supportelement 102 by extending past at least one end of support element 102.Optionally, porous structure 104 extends no more than 1 mm past the endof support element 102. Optionally, porous structure 104 extends over 1mm past the end of support element 102. Optionally, porous structure 104extends past only one end or both ends (as shown in FIG. 10) of supportelement 102.

In some exemplary embodiments of the invention, porous structure 104 isattached to support element 102 to prevent porous structure 104 fromunraveling and/or causing tissue irritation and/or avoiding dislodgmentof the porous structure from the support element during deployment.Optionally, the end of porous structure 104 is folded over the end ofsupport element 102 and attached, providing padding to a potentiallytrauma causing edge. Optionally, the end of porous structure 104 isfolded under itself and is held folded due to the pressure between thesupport element and the lumen. In an embodiment of the invention, atreatment, such as heat, is used to make the fold sharp and/orpermanent.

It should be understood that while an exemplary configuration ofenhanced stent apparatus is shown in FIGS. 1 and 2, other configurationscould possibly be used, including: a porous structure 104 over apharmaceutical eluting support element; a pharmaceutical eluting porousstructure over a support element 102; a pharmaceutical to eluting porousstructure over a pharmaceutical eluting support element; a supportelement in between at least two porous structures, optionally some orall eluting pharmaceuticals; and, an enhanced stent comprised of aplurality of layers which exhibit different optional characteristicssuch as degradation time and/or pharmaceutical elution. It should beunderstood that any of the above configurations include biodegradableand/or bioresorbable materials. Optionally, configurations are chosenfor specific treatment regimens indicated by the condition of thepatient.

In some exemplary embodiments of the invention, porous structure 104 isused to control the local pressure exerted by the enhanced stentapparatus on the body lumen wall. For example, by increasing ordecreasing the coverage area of the porous structure as it at leastpartially covers the stent, the pressure exerted by the enhanced stentapparatus per unit area can be altered. In some embodiments of theinvention, modification of the coverage area considers factors such asthe stiffness of support element 102 and the geometry and/or coveragearea of the support struts of support element 102. In an embodiment ofthe invention, pressure control is used to reduce the likelihood of theenhanced stent apparatus causing plaque to break off of the lumen wall.In some embodiments of the invention, pressure control is used to reducetissue trauma typically caused by stent implants, thereby enhancingprotection against stenosis/restenosis. Furthermore, in some embodimentsof the invention, support element 102 struts which could not be usedpreviously due to the likelihood of trauma to the lumen tissue canoptionally be used in combination with porous structure 104.

In some exemplary embodiments of the invention, bile ducts are treatedusing at least a porous structure as described herein. For example, thebile ducts often become congested with debris (e.g. cholesterol) whichrestricts flow. Treatment of the bile ducts using enhanced stentapparatus may increase the diameter of the bile ducts, improving theiroperation.

It is known that varying types of body lumens possess varying surfacetextures, both varying from each other, and sometimes within one type oflumen. Thus, in some exemplary embodiments of the invention, differentporous structures with varying surface texture configurations aremanufactured and/or used depending on the interior surface texture of alumen being treated. For example, peaks and valleys in a body lumen arefitted with counter peaks and valleys of a porous structure (i.e. porousstructure counter peak goes into lumen valley and porous structurecounter valley accepts lumen peak). Optionally, the counter peaks andvalleys are of the same magnitude as the peaks and valleys found in thelumen being treated.

It should be understood that the aperture size, the porous structurethickness, the fiber thickness (or French), and/or the coverage area arevaried for different applications. For example when treating thecarotids, debris of more than 100 microns should be prevented fromreaching the brain, thus the porous structure is designed such that whenstent is expanded, usually to about 8 millimeters, the majority ofaperture sizes are less than 100 microns. As another example, whentreating the coronaries larger debris (>100 microns) is not asproblematic, while the endotheliazation process and the non-restrictionof flow to side branches is more important. Thus for coronary arteryapplications, when the support element 102 is in an expanded position,usually about 3 millimeters in diameter, the apertures in the porousstructure are optionally larger than 100 microns and below 300 microns.In some embodiments of the invention, the rate of endothelium cellgrowth over porous structure may be modified by increasing and/ordecreasing fiber thickness and porous structure thickness.

In some exemplary embodiments of the invention, porous structure 104 isused with a balloon expandable support element 102. In some exemplaryembodiments of the invention, porous structure 104 is placed directly onan expandable balloon 802 without or with support element 102, forexample as shown in FIG. 8. In some exemplary embodiments of theinvention, the balloon catheter may extend past a proximal and/or distalend of support element 102. It is optionally desirable to provide porousstructure 104 which extends past the end of support element 102 toprovide a buffer between the balloon and the blood vessel, andoptionally to provide pharmaceutical treatment to regions to which theunderlying support element 102 does not extend, but may be exposed tothe balloon.

In an exemplary embodiment of the invention, porous structure 104 isunder 100 microns in thickness. In some exemplary embodiments of theinvention, the porous structure is less than 30 microns thick.Optionally, the porous structure is less than 10 microns in thickness.For example, the porous structure is less than 5 microns or 1 micronthick. Porous structure 104 is optionally comprised of at least onefine, thread-like fiber. In some exemplary embodiments of the invention,porous structure 104 is comprised of at least one fiber that is 40 nm to40 microns thick. Optionally, to the fiber thickness is similar to orless than the diameter of an endothelial cell to encourage endothelialcell growth between fibers and/or around at least one fiber. In anexemplary embodiment of the invention, a super-fiber is used toconstruct porous structure 104, wherein the super-fiber is made ofmultiple fibers braided together. Optionally, super-fibers are used toenhance the strength of porous structure 104.

In an exemplary embodiment of the invention, the fibers of porousstructure 104 are spun and/or knitted and/or woven and/or braided toprovide structure to and apertures 110 in porous structure 104.Optionally, the porous structure is woven in an even pattern.Optionally, the porous structure is constructed so that the fibers arerandomly positioned in porous structure 104. Optionally, polymer fibersare used to construct porous structure 104. Optionally, polymercoverings are applied to porous structure 102 and/or support element102. Exemplary porous structure manufacture is described in more detailin the “Methods of Manufacture” section below.

In an exemplary embodiment of the invention, the polymer covered porousstructure 104 is optionally made out of a closed interlocked designand/or an open interlocked design, or semi open design, similar totypical support element 102 designs. The open interlocked design has anadvantage when side branching is needed. When treating a junction of twoblood vessels, there is sometimes a need to introduce one stent throughthe side of another one. An open interlocked design allows such aprocedure, and when the porous structure is made of metal mesh, an openinterlocked design is utilized in order to allow easy side branchingstents. Optionally, using a biodegradable polymer coating on anon-biodegradable support element 102 leaves the support element 102embedded after the biodegradable polymer has degraded.

In an exemplary embodiment of the invention, porous structure 104 iscrimped to a small diameter while still maintaining its flexibility, toenable successful maneuverability through a patient's blood vessels tothe site where enhanced stent apparatus 100 is to be implanted. In anexemplary embodiment of the invention, porous structure 104 isexpandable to enable expansion of porous structure 104 with supportelement 102 upon deployment at a treatment site within a patient's bloodvessel. Optionally, expansion of porous structure 104 along thelongitudinal axis matches the expansion of support element 102 along thelongitudinal axis.

In an exemplary embodiment of the invention, at least porous structure104 is expandable without significant foreshortening or elongation ofthe length of porous structure 104. Optionally, porous structure 104expands differently than support element 102, for example using slidingconnections described herein. As described elsewhere herein, in aknitted embodiment of porous structure 104, expansion occurs at leastpartially as a result of the knitted structure, and not necessarilybecause of the elasticity of the fiber used in constructing porousstructure 104. In an embodiment of the invention, at least one fiberwhich comprises porous structure 104 is provided with slack duringmanufacture to provide additional fiber material when porous structure104 expands. FIG. 9 shows a perspective view of an enhanced stentapparatus 900. Enhanced stent apparatus 900 is provided withnon-stretchable wires 902, and stretchable elastomer fibers 904, inaccordance with an exemplary embodiment of the invention. Such anembodiment assists with the preservation of overall apparatus 900 lengthwhile allowing expandability and flexibility during implantation.

In an exemplary embodiment of the invention, an enhanced stent apparatusis provided which is comprised of at least an expandable support elementand an expandable porous structure. The support element is optionally astent, examples of which are known in the art for providing treatment toa wide range of body lumens. In an embodiment of the invention, theporous structure has structure which resembles to fishing net. In anembodiment of the invention, the porous structure is knitted from afiber approximately 15-20 microns in diameter, has a coverage area ofless than 20%, and which has aperture sizes approximately 150.times.200microns. In some embodiments of the invention, the porous structure isat least temporarily attached to support struts of the support elementby stitching. Optionally, the stitches are loose, allowing the porousstructure to slide on the support struts, for example to provide extraexpandability as described herein with respect to FIG. 16. In someembodiments of the invention, the stitching is biodegradable. In someembodiments of the invention, the support element and/or the porousstructure are adapted to elute pharmaceutical agents into the body lumenbeing treated.

In some embodiments of the invention, different characteristics of theenhanced stem apparatus are chosen based on the intended use ortreatment to be rendered. For example, aperture sizes are optionallychosen based on a desire to provide embolic shower protection againstdebris of a certain size. As another example, coverage area isoptionally selected for modifying local pressure on the lumen beingtreated. Many of these characteristics are interrelated, as describedherein and shown in FIG. 15, for example.

In an embodiment of the invention, porous structure 104 is flexible toallow the lumen to naturally change its diameter, to account forpressure changes in the lumen and/or to respond to muscular activity. Insome embodiments of the invention, the porous structure 104 divided intoa plurality of semi-independent sectors, which react differently tostimuli within or from the lumen. Optionally, the sectors are used toprevent banding of the lumen across the entire length of the porousstructure 104.

Exemplary Characteristics and Performance of Porous Structure

Manufacturing techniques, described in more detail below, such asknitting which provide slack to individual fibers, or sections, ofporous structure 104, enable porous structure 104 to optionally expandupon deployment up to 10 times its diameter at insertion (insertiondiameter is described in more detail below), in an embodiment of theinvention. For example, in coronary applications porous structure 104may expand from 1 mm to 3 mm in diameter. In other examples, porousstructure 104 may expand from 2 mm to 8 mm in carotid applications,while in brain applications porous structure 104 may expand from 0.3 mmto 2.5 mm. These numbers are approximate and are by way of example only.In an embodiment of the invention, expansion of porous structure 104 iseffectuated in at least one of three ways: 1) the knitted/braided/wovenstructure of porous structure 104 (including slack in the fibers andcurly fibers); 2) the fiber from which the porous structure 104 is madeis at least slightly elastic; 3) sliding connections (described below)between porous structure 104 and support element 102 permit shifting ofporous structure 104 during expansion with respect to support element102, within certain limits. In an embodiment of the invention, the fiberfrom which porous structure 104 is made is comprised of between 2% and80% of non-elastic materials. In some embodiments of the invention, theelastic material of the fiber from which porous structure 104 is madeallows for expansion up to 1000% its original size.

In some exemplary embodiments of the invention, porous structure 104exhibits a high durability when subjected to twisting, turning,compression and/or elongation, which allows porous structure 104 towithstand the delivery process through the patient's vasculature to atreatment site. In an embodiment of the invention, porous structure 104is loosely attached to the balloon at several locations and folded forinsertion into a lumen, such as depicted in FIG. 12; such aconfiguration is optionally used in conjunction with supportive element102. The folded porous structure 104 provides a reduced diameterapparatus for easier insertion into body lumens of the patient. Asdescribed below, porous structure 104 is at least temporarily fastenedto balloon to prevent porous structure 104 from becoming dislodgedduring implantation.

In some exemplary embodiments of the invention, 20% of the total area ofporous structure 104 is comprised of apertures having an approximatediameter no greater than 50, 200 or more than 200 microns in an expandedconfiguration. It is recognized that during the course of manufacturingthe porous structure, for example with certain manufacturing techniqueslike electrospinning and/or knitting, apertures created within theporous structure may overlap. This overlap effectively creates anaperture size which is smaller than specified. However, in someexemplary embodiments of the invention, the effective, nominal aperturesize is no greater than 50, 200 or more than 200 microns in diameter. Insome embodiments of the invention, aperture sizes are selected toencourage endothelial cell overgrowth at a certain rate.

It should be noted that shapes of apertures are likely to vary at leastsomewhat as a result of manufacture and/or desired properties of porousstructure 104. For example, in a knitted porous structure, apertures aremost likely to be roughly square. In contrast, use of a weavingtechnique to manufacture porous structure likely produce square and/orrectangular shaped apertures whereas a braided porous structure islikely to exhibit quadrilateral shaped apertures, such as in FIG. 7. Indescribing an approximate “diameter” of an aperture, it should berecognized that all, some or none of the apertures will be actualcircles, squares, rectangles and/or quadrilaterals capable of simplisticarea measurement using diameter. Therefore, description using diameteris merely an approximation to convey exemplary aperture sizes. Forexample, “diameter” could be the distance between two parallel sides ofa quadrilateral, such as a square or rectangle.

In some parts of the following description, aperture sizes describedherein are in reference to their size upon porous structure deploymentin a lumen. In other parts, the sizes refer to the aperture sizes whencrimped. Sometimes, the aperture sizes described herein refer to theirsize in a state intermediate a crimped and deployed configuration. Incontext, it should be easily perceived which of the above configurationsapplies, however, in the event it is not clear the aperture sizes couldbe considered as applying to expanded, crimped or intermediateconfigurations. When a fiber diameter is referred to, it relates to thefiber used to construct the porous structure 104. For example, if porousstructure 104 is constructed from a super-fiber comprised of a bundle of10 fibers each 2 microns in diameter, the overall super-fiber diameteris about 20 microns. Furthermore, it should be understood thatreferences to fiber diameter are for approximation and convenience onlyand does not imply that the fiber is necessarily round. Optionally,fiber sizes are measured in French sizes, for example 0.003 Fr.

Referring to FIG. 15, a graph 1500 is shown which correlates fiberthickness of porous structure with percentage of the coverage area of asupport element, for a porous structure with a fishing net typeconfiguration. It can be seen that the general trend is that as thefiber sizes get thinner, the amount of porous structure surface areadedicated to structure is reduced. In an embodiment of the invention, itis desirable to have under 25% coverage area. Optionally, porousstructure 104 exhibits less than 20% coverage area. In an embodiment ofthe invention, the coverage area of the porous structure is adapted tobe minimized while still performing an intended lumen treating function,such as those described herein. In some embodiments of the invention,the coverage area of porous structure 104 is minimized in order to avoidundesirable clinical side effects. For example, lumen tissue irritationand pyrogenic effects are considerations for minimizing the coveragearea and optionally other characteristics such as aperture size, porousstructure thickness and/or fiber thickness, of porous structure 104.

In some exemplary embodiments of the invention, the proportion ofstructure to apertures of porous structure 104, fiber size and/orapertures are sized in order to allow easy diffusion through porousstructure 104 and to facilitate growth of endothelial cells. Since thefiber 2202 diameters used in construction of porous structure 104 are onthe order of the size of the endothelial cells 2204, or smaller, asshown in FIG. 22, the integrity of the cells grown over the porousstructure will be much better than what is achieved in the prior art. Anindividual cell, statistically, will have a firm connection to the bloodvessel wall, since it is of the same order or larger than the fiberdiameter, thus anchoring itself, in an embodiment of the invention, inmore than one location to its native basalamina intimal layer andenabling better growth conditions. It is thus expected that the chanceof late or sub-acute thrombosis can be reduced over what is currentlyachieved when treatment is performed using a pharmaceutical elutingstent. In addition, porous structure 104 effectively acts as an embolicshower protection device, holding detached plaque in place, preventingit from traveling from the vessel wall into the blood stream. It shouldbe noted that porous structure 104 is configured, accounting for fiberthickness, porous structure thickness and/or aperture size such thatendothelial cells will overgrow porous structure 104, and optionallysupport element 102, in order to secure the enhanced stent in placeand/or insulate the foreign material of support element 102 and/orporous structure 104 from the bloodstream. In an exemplary embodiment ofthe invention, endothelial cell layer overgrowth of porous structure 104is established within hours of implantation. In an embodiment of theinvention, overgrowth is accomplished within this time frame due tocharacteristics of porous structure 104 as they relate to endothelialcells, for example, the overall thickness being on the same order of, orsmaller, than an individual endothelial cell. In some embodiments of theinvention, it is conceived that a patient's average stay in the hospitalafter a stenting procedure can be reduced as a result of the speed ofendotheliazation using enhanced stent apparatus. In addition, the speedand efficacy of pharmaceutical treatment can expected to be enhanced asa result of the rapid endotheliazation over at least porous structure104 of enhanced stent apparatus 100.

FIG. 23 shows a disadvantage of using prior art drug eluting stentswherein a clump of endothelium cells have become detached from the stentstrut 2304, revealing an exposed “island” 2302 of the stent. Sometimes aclump falls off strut 2304 due to poor adhesion of the endothelium cellsto the polymer coating of the strut 2304. Contributing to this pooradhesion, the stent strut 2304 is typically an order of magnitude largerthan a single endothelium cell, thereby necessitating the creation of alarge endothelium cell bridge to cross the strut. The exposed island2302 can serve as a seed for thrombosis development. In some embodimentsof the invention, porous structure 104 is constructed to reduce thelikelihood of endothelial cells falling from the porous structure,thereby reducing the chance of development of late or sub-acutethrombosis and exposure of support element 102 to substances within thelumen. For example, endothelial cell retention is optionally encouragedby constructing porous structure 104 from at least one fiber of athickness and with aperture sizes (to permit growth of endothelial celltherethrough), such as described herein. Optionally, endothelial cellsare encouraged to remain on the porous structure by using a fiber layerof a thickness such as those described herein. Optionally, the linearnature of a single fiber porous structure 104, such as shown in FIG. 22,reduces the possibility of a large clump of endothelial cells becomingdislodged. In an embodiment of the invention, porous structure 104,optionally imbued with a pharmaceutical, is placed on the interior of abare metal or drug eluting support element in order to reduce thethrombogenicity of the support element. For example, by encouragingendothelial cell growth thereover and/or by reducing the exposed surfacearea of the support element by covering a portion of it up.

As suggested above, using a thin fiber whose thickness is similar to, orsmaller than, the diameter of an endothelial cell enables an endothelialcell layer to grow over porous structure 104 while still being closelytied to the basal intima layer at least at two points of the endothelialcell, one point on each side of porous structure 104. In an embodimentof the invention, the anchoring effect of this basal intima layer on theendothelial cell layer reduces the chance of parts of the endothelialcell layer breaking off and entering the lumen. This, in effect, reducesthe chances of embolism in the patient and/or also reduces thelikelihood of foreign bodies (e.g. the stent and the porous structure)coming into contact and reacting with the contents of the lumen beingtreated. In the event that a clump of several endothelium cells fallfrom porous structure 104, exposing a piece of the fiber, it is believedthat there is a reduced chance of harm to the patient since the linear,single endothelial cell width geometry is not as thrombogenic as thatshown in FIG. 23, where a clump of endothelial cells at least severalcells in diameter has fallen off. In addition, the re-endotheliazationwill be faster on an exposed porous structure 104 than on the exposedstrut 2304 for at least the reason that in the case of the porousstructure 104, an endothelial cell layer is formed when just oneendothelial cell overgrows the endothelial cell sized fiber used toconstruct the porous structure. In contrast, endothelial cell layerovergrowth is only accomplished after multiple endothelial cells havecovered the exposed island.

In an embodiment of the invention, the reduced risk of late or sub-acutethrombosis by using porous structure 104 for pharmaceutical elutionoptionally allows for a duration and/or dosage reduction in the use ofanti-coagulants by the patient.

In some exemplary embodiments of the invention, fiber thickness, porousstructure thickness and/or aperture size are all separately varieddepending on the application of porous structure 104 and the needs ofthe patient. For example, in the coronary arteries it is sometimeshelpful to provide for good pharmaceutical dispersion. In such anexample, fibers comprising porous structure 104 are optionally locatedcloser together in order to allow for more complete transmission of apharmaceutical to patient.

In some exemplary embodiments, when large molecule drugs, which have apoor diffusion into the tissue, are used to fight restenosis, the porousstructure can be soaked and/or imbued with an appropriate drug in orderto better diffuse it. The maximum concentrations of most of the drugsused are rather limited due to side effects and over toxicity, and atthe same time the concentration is not enough in order to allow theoptimum pharmacokinetics in areas not covered by the stent struts. Theporous structure mesh, having a better geometrical cover of the stentarea, provides a better and more optimum pharmacokinetics to the wholearea covered by the stent. For example, when high Dalton-large moleculedrugs are used, or when liposomes are the carriers of the treatmentagents, or when the stereo-chemical structure of the drug is largeand/or complicated, and/or when the drug is hydrophobic, relatively evendistribution of the drug is highly desirable. In some exemplaryembodiments of the invention, pharmacokinetics are also optimizedbecause the drug is located on/in the fibers of porous structure 104,and is covered and sealed within an endothelium layer, which helps thedrug from being washed away by the blood.

In some exemplary embodiments of the invention, such as in a bypass veingraft, side branching is not an issue, therefore aperture sizes areoptionally made smaller, but not so small as to prevent endothelial cellgrowth therethrough. In another exemplary embodiment of the invention,such as in the carotid arteries, side branching is not generallyconsidered a problem, but catching debris is. Therefore, in someexemplary embodiments of the invention, the aperture sizes of porousstructure 104 are decreased to as little as 20 microns in diameter. Inother applications, the aperture size can be increased to 50, 100, 200or even more then 200 microns, depending on the application of enhancedstent apparatus 100.

In some exemplary embodiments of the invention, a plurality of porousstructures is used. Optionally, at least one porous structure is locatedon the interior of support element 102, inside the lumen of supportelement 102. Optionally, more than one porous structure is located onthe exterior surface of support element 102. In some exemplaryembodiments of the invention, at least some of the porous structureslocated on support element 102 are configured to be “in-phase” where theapertures of the porous structures coincide with one another.Optionally, the porous structures are “out-of-phase” where the aperturesare configured to not coincide with one another. In an exemplaryembodiment of the invention, an “out-of-phase” configuration is used toimprove contact surface area between porous structures and the lumeninterior surface. In an embodiment of the invention, increased contactsurface area can improve pharmacokinetics, reduce local pressure exertedby porous structure 104 on the lumen wall, improve embolic showerprotection and/or realize other advantageous effects. In some exemplaryembodiments of the invention, porous structure 104 is constructed in thesame shape and pattern as support element 102, but on a smaller scale.

Exemplary Materials of Manufacture

It should be noted that in some exemplary embodiments of the invention,a stretchable and/or expandable porous structure 104 is desired.Therefore, in some embodiments of the invention, materials are chosenwhich are either a) stretchable and/or b) can be used to manufacture aporous structure which is stretchable (e.g. a knitted structure). Insome exemplary embodiments of the invention, biodegradable (i.e. arebroken down by the body) and/or bioresorbable (i.e. are absorbed intothe body) materials are used. In addition, blends of materials are usedin accordance with some embodiments of the invention. In an embodimentof the invention, a material is chosen because it exhibits durabilityduring manufacture, deployment and/or use despite being thin. In anembodiment of the invention, other considerations for the material to beused are their biocompatibility, toxicity, hemocompatibility, andthrombogenicity.

Exemplary materials for manufacturing porous structure 104 includenatural-based materials such as modified cellulose and/or collagen. Insome embodiments of the invention, metal fibers are used to constructporous structure, optionally constructed of stainless steel, and/or CoCrand/or CoNi alloy among other possibilities. Optionally, the metalfibers used are coated with at least one polymer. In some embodiments ofthe invention, porous structure is manufactured from a shape memoryalloy, such as nitinol. Optionally, carbon fiber is added to porousstructure 104 in order to improve strength characteristics of porousstructure 104. Optionally, glass fiber is added to porous structure 104in order to improve strength characteristics of porous structure 104.Optionally, a durable, resorbable and/or degradable fiber is added toporous structure 104 in order to improve strength and durabilitycharacteristics of the fiber during manufacture, which is degraded orresorbed or washed away to leave a thinner porous structure 104.

In an embodiment of the invention, some polymer fibers are chosen foruse in constructing porous structure 104 because they are elastic,biocompatible, hemocompatible, can be made not to stick to an expandableangioplasty-type balloon catheter, to stick to endothelium tissue, areselectably bio-stable and/or biodegradable, exhibit the requisitemechanical strength, are sterilizable, have a high temperaturetransformation zone (solid and non sticky at 37° C.), are capable ofhosting an effective amount of pharmaceuticals, and/or can releaseembedded pharmaceuticals at a controlled rate. In some exemplaryembodiments of the invention, other materials which exhibit some or allof these properties are optionally used to construct porous structure104. Optionally, coatings are put on porous structure 104, comprised ofmaterials which exhibit some or all of these properties.

Polymer fibers are optionally made out of any of the followingmaterials: thermoplastic polymers for example polyethylene terephthalate(PET), polyolefin, oxidized acrylic, PTFE, polyethylene co-vinylacetate, polyethylene elastomer, PEO-PBT, PEO-PLA, PBMA, polyurethane,Carbosil (PTG product), medical grade polycarbonate urethanes, Nylon,PEEK-Optima, carboxylic acid moiety comprising one or more of a polyacrylic acid, a poly methacrylic acid, a maleic acid, a helonic acid, ataconic acid and/or combinations and/or esters of these monomers,thermoplastic polymers, thermosetic polymers, polyolefin elastomers,polyesters, polyurethanes, polyfluoropolymers, and/or nylon. Optionally,the fibers are constructed of an elastomer. Optionally, the fibers areconstructed of a coated fiber with a drug and polymer coating mixed toget a predetermined drug release characteristic, either coating over ametal and/or over a polymer fiber. Optionally, the fibers areconstructed of other materials than the exemplary materials listedabove. Exemplary polymers which are optionally used for this purpose aremanufactured by Cordis®, Surmodix®, Boston Scientific®, Abbott® andHemoteq® Polymers. Optionally, these polymers are selected for at leastone of the reasons specified in the paragraph above. Optionally, thecoating is used to facilitate the elution of pharmaceuticals from porousstructure 104.

In some embodiments of the invention, the porous structure is made outof a resorbable/degradable polymer such as poly lactic-co-polyglycolic(“PLGA”) copolymers, or any other degradable copolymeric combination,such as polycaprolactone (“PCL”), polygluconate, polylacticacid-polyethylene oxide copolymers, poly(hydroxybutyrate),polyanhydride, poly-phosphoester, poly(amino acids), poly-L-lactide,poly-D-lactide, polyglycolide, poly(alpha-hydroxy acid) and combinationsthereof.

In some embodiments of the invention, porous structure 104 is comprisedof a material which plastically or elastically deforms when a sufficientamount of radial pressure is applied to it, for example by anangioplasty balloon.

Exemplary Methods of Manufacture

Many of the methods and orientations described herein are designed toprovide a porous structure which exhibits at least some expandablequality. Porous structure 104 is optionally adapted and constructed tostretch as it is being deployed within the lumen being treated. In someexemplary embodiments of the invention, porous structure 104 is providedwith stretchability in order to ease positioning porous structure 104 ona balloon and/or support element 102.

In an exemplary embodiment of the invention, weaving, braiding and/orknitting results in some or all the elasticity of the porous structurebeing achieved due to the structure of the interlaced and/or crimpedand/or textured fibers (curly, slack). This can be achieved by materialelongation properties securing the porous structure to the stent. Insome exemplary embodiments of the invention, a porous structure is madeby combining several interlacing techniques such as knitting over abraided porous structure or braiding over a knitted porous structure. Insome embodiments of the invention, multiple layers are combined and/orcreated using these techniques. In some exemplary embodiments of theinvention, a warp knitted porous structure with “laid in” yarns is used.In some exemplary embodiments of the invention, a porous structure iswoven using elastomeric or crimped weft to obtain radial elasticity.

In some exemplary embodiments of the invention, the porous structure ismanufactured by combining several techniques such as knitting over abraided porous structure or braiding over a knitted porous structure. Insome exemplary embodiments of the invention, a weft knitted porousstructure with “laid in” yarns is used. In some exemplary embodiments ofthe invention, a porous structure is woven using elastomeric and/orcrimped weft to obtain radial elasticity. Optionally, porous structureis comprised of at least one fiber oriented generally parallel to thesupport element's longitudinal axis.

In an exemplary embodiment of the invention, a manufactured porousstructure is added as a cover to support element 102. Optionally, porousstructure 104 is used separately from support element 102, which isoptionally not used for stenting. In some exemplary embodiments of theinvention, porous structure 104 is manufactured directly onto supportelement 102.

In an exemplary embodiment of the invention, porous structure 104 ismanufactured by a knitting technique known to those skilled in theknitting art for non-analogous arts, such as clothing manufacturing andtextiles. Knitting of porous structure 104 is optionally performed byheads having between 20 and 35 needles. Optionally, the head used hasbetween 30 and 45 needles. Optionally, the head used has between 35 and80 needles. An example of the effect of head size on the porousstructure can be seen in FIG. 15, described above, in which a 22 sizehead and a 35 size head are graphed. In FIG. 15, the needle gauges are40.

In some embodiments of the invention, the shape and/or size of the knitis controlled by controlling the tension on the fiber being used forknitting. For example to create a knit with larger eyes, slack isprovided to the fiber during knitting. Optionally, the fiber iscontrolled during knitting to achieve a circular shaped eye when porousstructure 104 is expanded. In an embodiment of the invention,pre-tension on the fiber during knitting is approximately 10-20 grams.In some embodiments of the invention, post-tension on the fiber duringknitting is 15-25 grams. The stitch length is between 300 and 400microns, in an exemplary embodiment of the invention. In someembodiments of the invention, the knitting machine is run at arelatively slow speed. For example, the knitting machine is run at 10%of speed capacity using a Lamb Knitting Machine Corp. System Model WK6with a special modification of speed operation measured by percentage.

In an exemplary embodiment of the invention, a fiber or a super-fiberyarn with a specific fineness, or a range of fineness, between 5 and 100microns is used to manufacture a knit porous structure. Optionally, yarnwith a fineness of 10 to 20 microns is used to manufacture a knit porousstructure. Optionally, the yarn is finer than 5 microns. Yarn finenessis often referred to in textile terms by “Tex”. This is the weight ingrams of 1000 meters of the yarn. In an exemplary embodiment of theinvention, yarn ranging from 0.3 Tex to 10 Tex is used to manufactureporous structure. In some embodiments of the invention, a specific yarnfineness is chosen based on the desired porous structure 104characteristics. For example, a 0.5 Tex yarn using a 22 gauge needlehead will, in some embodiments, produce a porous structure withapproximately 12% coverage area.

An exemplary resulting porous structure using the above components andtechniques, should have 5 to 50 courses per cm. Optionally, 20 to 45courses per cm are manufactured. Optionally, a porous structure with30-35 courses per cm is manufactured. FIG. 5 illustrates a knittedporous structure 104 and support element 102 in a crimped, closedposition. FIG. 6A illustrates a knitted porous structure 104 laid on topof a support element 102 in an open position. FIG. 6B shows exemplaryknitting in detail.

In another exemplary embodiment of the invention, weaving techniques areused to manufacture porous structure 104. Narrow needle looms as well asconventional narrow looms can be configured to produce woven tubularstructures. In weaving, at least two layers of warp yarns are interlacedwith intersecting fill yarns.

By carrying the fill yarn alternately back and forth across two layersof warp yarns, a tubular shape is created. The size and shape of theweave are optionally controlled by determining the warp and/or filldensity, the interlacing pattern and/or frequency, the yarn tensionand/or the yarn dimensions and/or elastic properties. The types ofweaves used for a porous structure are optionally one of “plain”,“basket”, “twill”, “sateen”, “leno” and/or “jacquard”. Optionally, allof the fibers of porous structure are the same. Alternatively, warp andweft fibers of a weave are not constructed of the same materials.Optionally, different materials are used to take advantage of theinherent properties of the different materials, for example one materialmay be elastic and a different material may have a high tensilestrength. Optionally, warp fibers are coated and/or are pharmaceuticaleluting while the weft fibers are not, or vice versa.

In another exemplary embodiment of the invention, braiding techniquesare used to manufacture porous structure 104, for example as describedin Knitting Technology, D. J. Spencer—ed., Woodhead Publishing Limited,Abington Hall, Abington, Cambridge, CB1 6AH, England, the disclosure ofwhich is incorporated herein by express reference thereto. Braidingmachines are optionally used to interlace yarns at a variety ofintersecting angles. In braiding, multiple yarns are fed to aninterlacing zone. Interlacing is optionally achieved by rotation of theyarn spools or by a reciprocating needle bed. The size and shape of thebraid is optionally controlled by the number of yarns, the interlacingpattern and/or angle and/or the yarn dimensions and/or elasticproperties. Optionally, all of the fibers of porous structure are thesame. Optionally, warp and weft fibers of a braid are not constructed ofthe same materials, for example where weft fibers are used to providestrength and warp fibers are used to provide stretchability of thebraid.

In another exemplary embodiment of the invention, porous structure 104is manufactured by an electrospinning process. Electrospinning is atechnique which utilizes a charged polymer solution (or melt) that isfed through a small opening or nozzle (usually a needle or pipette tip).Because of its charge, the solution is drawn toward a groundedcollecting plate (usually a metal screen, plate, or rotating mandrel),typically 5-30 cm away, as a jet. Optionally, support element 102 isplaced on a delivery catheter which is used as a mandrel. During thejet's travel, the solvent gradually evaporates, and a charged polymerfiber is left to accumulate on the grounded target. The charge on thefibers eventually dissipates into the surrounding environment. Theresulting product is a non-woven fiber porous structure that is composedof tiny fibers with diameters between approximately 40 nanometers and 40microns (e.g. a felt), depending on the size of the fibers input intothe system. If the target is allowed to move with respect to the nozzleposition, such as by rotating and/or moving the mandrel along its longeraxis, specific fiber orientations (parallel alignment or a randomalignment, as examples) can be achieved. In some exemplary embodimentsof the invention, porous structure 104 is spun in a helical coil patternonto the mandrel or support element 102. Optionally, porous structure104 is comprised of a plurality of helical coil patterns, constructed bymoving the mandrel back and forth, such as depicted in FIG. 4.Optionally, porous structure 104 is constructed with fibers orientedsubstantially parallel to central axis 106. Optionally, porous structure104 is constructed with fibers oriented substantially perpendicular tocentral axis 106. Optionally, porous structure 104 is constructed withfibers oriented in a combination of any of the orientations described orsuggested herein. The mechanical properties of the porous structure areoptionally altered by varying the fiber diameter and orientationdepending on the requirements for treating a patient. For example, insome embodiments of the invention, a laser is used to cut specificaperture sizes and/or to ensure that the apertures traverse from theexterior side of porous structure 104 to the interior side of porousstructure 104. Optionally, solvent is used to modify aperture sizes.

Optionally, portions of catheter are masked in order to preventaccidental coverage of the delivery catheter by porous structure 104.Optionally, support element 102 is coated with an adhesive and/or apharmaceutical agent prior to putting the porous structure 104 on thetop of support element 102. In some exemplary embodiments of theinvention, the material used to produce the porous structure 104 isimbued with pharmaceutical agents. Optionally, pharmaceutical agents areembedded in the material coating the porous structure 104. In anexemplary embodiment of the invention, porous structure 104 is comprisedof at least one inner coating proximal to supporting structure 102 whichexhibits different properties than an external coating proximal topatient's blood vessel. For example, the inner coating is optionallyconfigured to avoid adhesion to the delivery catheter and/or supportstructure. Optionally, inner coating is configured to adhere to supportelement 102, but not to delivery catheter.

In some embodiments of the invention, porous structure 104 is designedto be less sensitive to foreshortening and elongation forces as porousstructure 104 expands upon deployment. This is in part due to theknitted nature of porous structure 104, in some embodiments. Thisproperty allows porous structure 104 to be secured to support element102 at its ends, rather than in another location, such as the middle asdescribed in U.S. App. No. 2005/0038503 to Greenhalgh et al., thedescription of which is incorporated herein by express referencethereto.

In some exemplary embodiments of the invention, a porous structure ismanufactured in an at least partially open, wide diameter, condition. Insome exemplary embodiments of the invention, the at least partiallystretched porous structure is reduced to a smaller diameter, byheat-setting, crimping and/or folding, after manufacture.

In an embodiment of the invention, the diameter of the at leastpartially stretched porous structure is reduced mechanically.Optionally, a funnel 1304 shown in FIG. 13, is used to reduce thediameter of the knitted porous structure 1302, during the manufacturethe porous structure. A knitted porous structure 1302 is drawn down fromthe knitting zone into a narrowing bore, funnel 1304. This results in afinal porous structure diameter that is controllably smaller than thediameter of the needle bed. FIG. 14, illustrates how a porous structureis manufactured using a stretched rubber tube 1402. In this method, theporous structure 1400 is tightly inserted onto a pre-radially stretchedtube 1402, and then the tube is relaxed, compressing the porousstructure and creating a smaller aperture sized porous structure, thesize of which is controlled by the stretch ratio of the rubber tube.

Referring to FIG. 18, an embodiment is shown in which porous structure104 is folded in “n” substantially folds, the folds used to reduce theoverall diameter of enhanced stent apparatus 100 for easier insertionand navigation through the patient. Optionally, the folds are towardsthe same direction. In an embodiment of the invention, a folded porousstructure 104 is at least temporarily secured to support element 102.FIG. 11 shows an alternate folded configuration from a perspective view.

An additional or alternative embodiment to folding includes heat settinga polymer comprised porous structure 104 to support structure 102. In anembodiment of the invention, heat setting is used when porous structure104 is comprised of at least one polymer material. Determination of heatsetting conditions is related to the polymer's heat transitiontemperatures, in an embodiment of the invention. Heat setting isperformed in the temperature range between T_(g) and T_(m) of thepolymer. At this range the polymer becomes amorphous and is shrunk tosupport element 102, establishing an overall enhanced stent apparatus100 radius that is not much more than the support element 102 radius.For example, porous structure 104 adds less than 10 microns in diametertotal to support element 102 which is 1 mm in diameter, in someembodiments of the invention. At T_(m) the polymer turns into a viscousliquid which loses its mechanical integrity and will stick to supportelement 102 surface. For example, polyethyleneterephthalate (PET) has aT_(g) of 70° C. and a T_(m) of 265° C., therefore the heat settemperature somewhere within that range, in an embodiment of theinvention, is 200° C. Using temperatures higher than T_(m) for heatsetting can cause thermal degradation, which results in polymeric chainscission, unzipping of the polymer and/or producing a large array ofoligomeric material that changes the mechanical properties of porousstructure 104 and/or releases poisonous and/or non-biocompatiblematerials, causing an inflammatory reaction in the patient. Otherexemplary polymers which can be used in heat setting are below in Table1 (not an exhaustive list):

TABLE 1 TABLE-US-00001 Exemplary polymers and temperatures for heatsetting Material name Material name T_(g) T_(m) set temp. PP  18° C.165° C. 140° C. NYLON 6,6  80° C. 256° C. 210° C. PTFE 150° C. 330° C.300° C. PVA 100° C. 230° C. 190° C. Polyurethanes  70° C. 120° C. 100°C. PLLA  60° C. 175° C. 100° C.

Another additional or alternative embodiment to folding includescrimping using at least a crimped support element 102 in combinationwith porous structure 104. In some embodiments of the invention, porousstructure 104 is crimped with support element 102. In an embodiment ofthe invention, crimping of porous structure 104 and support element 102is performed when it is desirable to reduce the overall diameter ofenhanced stent apparatus 100. For example, a reduced diameter enhancedstent apparatus 100 allows for easier insertion and navigation of theapparatus to the treatment site. In some embodiments of the invention,at least a crimped support element 102 provides an object withrelatively stable mechanical properties for more predictable movementduring insertion and navigation.

Optionally, porous structure 104 is made on a non-crimped supportelement 102. A non-crimped support element 102 can be expanded orsemi-expanded during manufacture. In an exemplary embodiment of theinvention, porous structure 104 and support element 102 are crimpedtogether. Optionally, excess porous structure 104 material, which iscreated as a result of reducing the profile of support element 102during crimping, is folded with support element 102, such as shown inFIG. 18. In some exemplary embodiments of the invention, porousstructure 104 is made on a crimped or partially crimped supportstructure 102. When manufacturing a porous structure for placement on analready crimped support structure, consideration may be given toproviding a porous structure which is sufficiently stretchable to expandwith the radial expansion of the support structure, when implanted at atreatment site within a lumen. In some embodiments of the invention, aporous structure is placed on a support element already positioned on anangioplasty balloon.

In electrospinning embodiments of the invention, the procedure formanufacturing a porous structure on a balloon is similar tomanufacturing on a stent or mandrel. For example, varying the motion ofthe balloon with respect to the electrospinning device allows themanufacture of specific fiber orientations.

Exemplary Methods for Coating a Fiber

In another exemplary embodiment of the invention, a manufacturingtechnique is used to coat a fiber that porous structure 104 is comprisedof with at least one polymer layer. For example, a dipping technique,shown in FIG. 19, using a biocompatible, hemocompatible, biostableand/or biodegradable polymer dissolved in an organic solvent is utilizedto create a dipping solution 1906 for use in coating the fibercomprising porous structure 104. The fiber to be coated is optionallyplaced in a spool 1902, from which the fiber 1904 is drawn to formporous structure 104. Additives such as drugs, biological components,enzymes, growth factors, and/or any other additive mentioned herein orknown in the art, may be incorporated into fiber 1904 during themanufacturing process, for example by placing them in solution 1906 andpassing fiber 1904 through solution 1906. In an embodiment of theinvention, at least one layer is used in order to control thedrug/biological additive's release. For example, more than one solutiontank may be provided for fiber 1904 to pass through during manufacture.Fiber 1904 is optionally moved into a drying oven 1908 with anoperational temperature range from 37-70° C. (in some embodiments of theinvention) depending on the drug used, to dry solution 1906 onto fiber1904. In an exemplary embodiment of the invention, fiber 1904 is thenused by a knitting system to 1910 to manufacture porous structure 104.Optionally, knitting system 1910 is the Lamb Knitting Machine Corp.System Model WK6. Optionally, porous structure 104 is coated with apolymer layer after it has been manufactured.

In some exemplary embodiments of the invention, support element 102 andporous structure 104 are coated with an additional substance.Optionally, the additional substance is a polymer. Optionally, theadditional substance is drug eluting. Optionally, the coating ishyaluronic acid. Alternatively or additionally, the coating ishyaluronan. Optionally, a different non-woven technology such as wetand/or dry spinning is used to manufacture porous structure 104. In someembodiments of the invention, additional coatings are added to achievedifferent effects, for example timed release of pharmaceutical agentsand/or release of a plurality of agents at different times.

Exemplary Methods for Mounting Porous Structure to Support Element

In some embodiments of the invention, porous structure 104 is at leasttemporarily secured to support element 102. Advantages of securingporous structure 104 to support element 102, at least temporarily,include: prevention of unraveling and/or run out of fiber from theporous structure weave, dislodgement and/or slipping of porous structure104 with respect to support element 102 during insertion, deliveryand/or deployment. Optionally, support element 102 and porous structure104 are not secured together using an adhesive and/or other securingmeans despite being in a coaxial and proximate relationship in manyembodiments.

In some exemplary embodiments of the invention, where support element102 is optionally coated with a polymer, support element 102 and porousstructure 104 are attached together by curing at the same time thepolymer support element coating and the polymer comprised porousstructure, and/or coated porous structure, thus adhering the polymerstogether. Optionally, pressure and/or heat is used to adhere a polymercoated support element 102 to a non-coated or polymer coated porousstructure 104, for example when they are both hot. In some exemplaryembodiments of the invention, porous structure 104 is comprised of twocomponents, an external component and an internal component, relative tosupport element 102. Upon the simultaneous curing of the external andinternal components, the polymers of which both are comprised to adheretogether, thereby securing porous structure 104 to support element 102,which is located between the components.

In an exemplary embodiment of the invention, porous structure 104 issecured to support element 102 in order to avoid porous structuremigration, but not limit porous structure 104 and/or support element 102expandability.

In some exemplary embodiments of the invention, an adhesive is used tobond support element 102 and porous structure 104 together. Optionally,porous structure 104 is glued to support element 102 utilizing anynatural and/or synthetic bio compatible adhesive, such as cyanocrylate,thermo plastic elastomers, silanes, laminin, albumin and/or fibrinogenand/or PEG-PEG adhesive, and/or polyurethane adhesive and/or any othersuitable compatible polymeric material. Optionally, when porousstructure 104 is glued to support element 102, wherein the supportelement 102 is a drug eluting stent, the same polymer as used for theelution of the drug is used for attachment of porous structure 104 tosupport element 102.

In an embodiment of the invention, porous structure 104 is attached tosupport element 102 at a plurality of points. Optionally, the pluralityof points defines a pattern, such as a line or zigzag of points.Optionally, porous structure 104 compresses onto support element 102 tomaintain an attachment to support element 102. Optionally, the porousstructure is held in place on support element at least partially byfrictional forces. Optionally, porous structure 104 is sewn and/ormechanically entangled onto support element 102. Optionally, heating,pressure, laser welding, UV curing and/or ultrasound are used astechniques to secure porous structure 104 to support element 102.Optionally, a primer, such as parylene, is used on support element 102prior to adhering porous structure 104 to it in order to enhancecohesion.

In some exemplary embodiments of the invention, elastic and/orexpandable o- and/or c-rings are used to hold porous structure 104 onsupport element 102. Optionally, c-rings are used to avoid hamperingexpandability of porous structure 104. Optionally, the rings are used toat least temporarily secure and/or apply friction to each end of porousstructure 104 to support element 102. Optionally, the rings are coatedand/or embedded with pharmaceuticals for elution, such as describedherein. Optionally, the rings are constructed of a polymer basedmaterial. In some exemplary embodiments of the invention, porousstructure 104 is tied to support element 102, optionally using fibers ofporous structure 104. In an exemplary embodiment of the invention, aslip ring 2102 is used to secure porous structure 104 to support element102, as shown in FIGS. 21A and B. Slip ring 2102 is adapted to expandwith porous structure 104 and support element 102 when they are expandedupon deployment at a lumen treatment site. Optionally, slip ring 2102 isflexible but is rigid enough to secure porous structure 104 to supportelement 102. In an embodiment of the invention, slip ring 2102 is coiledaround enhanced stent apparatus 100 when it is in a reduced profileconfiguration such that slip ring 2102 overlaps itself at leastpartially. Upon deployment, shown in FIG. 21B, support element 102 andporous structure 104 are expanded to provide treatment to the lumen. Inan embodiment of the invention, slip ring 2102 expands with them whilemaintaining sufficient pressure on porous structure 104 to retain it tosupport element 102. In an embodiment of the invention, the overlappingportion of slip ring 2102 is reduced as a result of the overall increasein diameter of the slip ring 2102. Optionally, slip ring 2102 iscomprised of a biodegradable and/or bioresorbable material. In someembodiments of the invention, slip ring 2102 is under 25 microns thick.Optionally, slip ring 2102 is under 15 microns thick. Optionally, slipring 2102 is under 10 microns thick.

Referring to FIG. 16, an embodiment of the invention is shown in whichporous structure 104 is attached to support element 102 using a slidingconnection 1602. In an exemplary embodiment of the invention, thesliding connection is established by attaching at least one loop 1604 ofporous structure 104 to support element 102 in a condition that preventsthe two from becoming separated, but is loose enough to allow sliding ofporous structure 104 with respect to support element 102. In anembodiment of the invention, a loose stitch is used to attach porousstructure 104 to support element 102 in a sliding connection. In anembodiment of the invention, expansion of porous structure 104 isassisted by utilizing the sliding nature of the connection 1602. Forexample, porous structure 104 is secured to the outermost strut 1606 ofsupport element 102 at its most outlying position 1608. In an embodimentof the invention, on the other side of support element 102 porousstructure 104 is also attached to the outermost strut at its mostoutlying position. When support element 102 and porous structure 104 areexpanded during deployment, porous structure 104 is afforded additionalexpandability, in relation to a pre-expanded configuration, as thesliding connection 1602 moves from the most outlying position 1608 onoutermost strut 1606 to an innermost position 1610. The distance 1612,about 1 mm to 6 mm in an embodiment of the invention, from the mostoutlying position 1608 to innermost position 1610 provides additionalexpandability to porous structure 104. Optionally, sliding is preventedby securing porous structure 104 to strut 1606 at innermost position1610 as well as most outlying position 1608. Optionally, sliding isprevented by tightening the connection between the two, for example byproviding a tighter stitch.

In some embodiments of the invention, porous structure 104 is tied tosupport element 102 using any one of thumb, square, reef, or doublesurgeon's knots. Optionally, the at least one fiber used to constructporous structure 104 is used to tie porous structure 104 to supportelement 102. FIG. 17 shows an exemplary method for attaching porousstructure 104 to support element 102 using knotting. It can be seen thata knotting fiber 1702 is used to secure porous structure 104 to supportelement 102 at various points along a support element strut 1704.Optionally, knotting fiber 1702 is threaded through a plurality of eyes1706 and over support element strut 1704 wherein a knot 1708 is tied tosecure porous structure 104 to support element 102 at least some of theeyes.

As mentioned above, in some embodiments of the invention, securingporous structure 104 to support element 102 is also used to reduce thelikelihood of run outs and/or porous structure unraveling. In anembodiment of the invention, run outs and/or porous structure unravelingare to be avoided for at least the reasons of: avoiding porous structureprotrusion into the lumen and/or rendering porous structure ineffectivefor intended treatment of the lumen. In an embodiment of the invention,porous structure 104 is secured to support element 102 at the ends ofsupport element 102, at least some intersections where porous structure104 and support element 102 overlap, or both and/or every eye at bothends. Any of the methodologies of securing described above areoptionally used to secure porous structure 104 to support element 102 toprevent run outs and/or unraveling.

In an exemplary embodiment of the invention, porous structure 104 istreated to supply temporary enhanced adhesion to support element 102during implantation.

For example, enhanced stent apparatus 100 is optionally dipped in aliquid which causes porous structure 104 to adhere to support element102. Optionally, this adherence is due to surface tension of the liquid.Optionally, this adherence is due to temporary shrinkage of porousstructure 104, which secures it to support element 102 more tightly. Insome exemplary embodiments of the invention, temporary cohesion is usedto prevent porous structure 104 from slipping off of support element 102as a result of frictional stress experienced during navigation of thevasculature during implantation.

General Pharmacological Usage

Alternatively or additionally to the physical prevention of debris fromentering the bloodstream, porous structure 104 optionally containspharmaceuticals designed to treat a variety of ailments. In someexemplary embodiments of the invention, pharmaceuticals are optionallyprovided including one or more pharmacological agents for encouragingcell and/or liposomal growth and/or other endothelial cell growthfactors, anti-proliferative, anti-thrombotic, anti-coagulant and/oranti-platelet effects, tissue engineering factors, immunomodulators,antioxidants, antisense oligonucleotides, collagen inhibitors,hydrophobic pharmaceuticals, hydrophilic pharmaceuticals and/orendothelial cell seeding substances. Optionally, pharmacological therapyrendered from a porous structure is used to accelerate vein to arteryconversion. Specific examples of pharmaceuticals that are optionallyused with porous structure 104 include: anti-proliferative agents likesirolimus, zolimus or zotarolimus (ABT-578®), paclitaxel and othertaxanes, tacrolimus, everolimus, vincritine, viblastine, HMG-CoAreductase inhibitors, doxorubicin, colchicine, actinomycin D, mitomycinC, cycloporine, and/or mycophenolic acid, triazolopyrimidine and itsderivatives (i.e. Trapidil®, a coronary vasodilating drug); intrapide,glucocorticoids like dexamethasone, methylprednisolone, and/or gammainterferon; antithrombotics like heparin, heparin-like dextranderivatives, acid citrate dextrose, coumadin, warfarin, streptokinase,anistreplase, tissue plasminogen activator (tPA), urokinase and/orabciximab; antioxidants like probucol; growth factor inhibitors liketranilast and/or angiopeptin; antisense oligonucleotides like c-mycand/or c-myb; collagen inhibitors like halofuginone and/or batimistat;liposomes; gemcitabine (i.e. Gemzar®); steroids and corticosteroids forexample cortisone and prednisone; cortisone, prednisone; sirolimus(Rapamycin®); statin drugs like lovastatin and/or simvastatin (i.e.Zocor®); VEGF; FGF-2; micro carriers containing endothelial cells;genes; DNA; endothelial cell seeds; and/or hydrogels containingendothelial cells.

Typically, stents (i.e. support elements) which provide pharmaceuticaltreatment only have the pharmaceutical embedded on the structure of thestent, in particular on the stent struts. This structure is typicallyminimized in order to provide flexibility and reduce cost, among otherreasons. As a result of a minimized support element structure, thestruts of the structure are usually spaced widely apart. Thus, when thestent is in situ, and pharmaceuticals are released into the patient fromthe stent, the pharmaceutical is only diffused from the widely spacedstruts. This prevents even distribution of the pharmaceutical over theentire length of the stent. In addition, stent struts are typicallylarge in relation to endothelial cells and therefore formation of acovering endothelial cell layer typically takes on the order of days orweeks, rendering pharmaceutical elution into body tissues delayed and/orineffective (due to a number of reasons, including the pharmaceuticalbeing washed away by fluids flowing in the lumen before the endothelialcell layer covers the stent).

In contrast, usage of a pharmaceutical enhanced porous structure, suchas described herein, to cover the stent, including the struts, providesfar more surface area in contact with the inner wall of the patient'sblood vessel, thereby enabling more diffusion to take place. Incomparison to conventional techniques for stent deliveredpharmaceuticals, lower concentrations of pharmaceutical are optionallyused with the present invention because of its improvedtherapy-rendering surface area. In an embodiment of the invention,improved delivery by the presently described invention allows for lowerdoses of pharmaceutical to be used in order to render the same relativeamount of treatment, and reduce the overall dosage needed in order toobtain the same results, thus reducing possible side effects. Forexample, a currently recommended concentration of taxol on a drugeluting stent is around 1 μg/mm² of stent surface. In contrast, aconcentration of 0.5 μg/mm² is optionally used with porous structure104, due to its increased treatment rendering surface area. Optionally,the concentration is less than 0.5 μg/mm². As another example, typicalconcentrations of rapamycin and ‘limus drugs today are around 140μg/mm², however, using the herein described porous structure 104 aconcentration of 80 μg/mm² is optionally used to achieve the sametherapeutic effect. In some exemplary embodiments of the invention, aslittle as 10 μg/mm² is optionally, used to achieve the same therapeuticeffect. In some exemplary embodiments of the invention, concentrationsof pharmaceutical embedded on porous structure are up to 15 times lessthan conventionally used today.

In conventional stents, at the struts, the pharmaceutical may notpropagate far enough and/or without effect into the vascular wall, ormay overdose a particular section of the vascular wall, withoutsufficient propagation laterally to the rest of the inner surface whereit is needed. Having additional surface area more evenly covering thestent surface area, porous structure 104 can deliver drugs in a morelocally homogenous way. Optionally, there is an axial profile change indosage. Since distribution of the drug into the tissue is governed bydiffusion, and since the amount of dosage concentration on the struts islimiting due to over toxicity and side effects, spreading the drug in amore even manner is very helpful for obtaining better pharmacokinetics.

In an exemplary embodiment of the invention, pharmaceuticals to beadministered to patient are located in and/or on the fibers of porousstructure 104. Examples of where and how pharmaceuticals are optionallylocated in and/or on the fibers of porous structure 104 and/or elutedinclude:

1. depositing pharmaceutical in the apertures of porous structure;

2. mixing pharmaceutical particles into fibers of porous structure atfiber creation;

3. applying pharmaceutical topically to the porous structure, such as byspraying;

4. dipping porous structure into a solution containing a pharmaceuticaladditive, thereby depositing the additive on and/or in the fibers of theporous structure;

5. encapsulating a pharmaceutical additive on porous structure,optionally using a thermal process;

6. grafting a pharmaceutical additive onto porous structure using plasmatreatment;

7. etching a pharmaceutical additive into porous structure, for examplevia spattering or coating;

8. transferring a pharmaceutical additive to porous structure usingconcentration differences between the porous structure and an additivecontaining substance, for example by adhering micro carriers containingto pharmaceutical additive to a porous structure allowing theirmigration into the porous structure;

9. any method known to those skilled in the art, such as shown in U.S.Pat. App. No. 2004/0030377 to Dubson et al., U.S. Pat. App No.2005/0187140 to Hunter et al., U.S. Pat. App. No. 2004/0236407 toFierens et al., U.S. Pat. No. 6,902,522, to Walsh, et al., U.S. Pat. No.6,669,961 to Kim, et al., U.S. Pat. No. 6,447,796 to Vook et al., U.S.Pat. No. 6,369,039 to Palasis et al., U.S. Pat. No. 6,939,374 to Banik,et al., and U.S. Pat. No. 6,919,100 to Narayanan, the contents of whichare incorporated herein by express reference thereto;

10. elution of the drug from a polymer coating the porous structurefibers;

11. elution of the drug from the polymer from which the porous structureis constructed; and,

12. incorporating the drug in a biodegradable polymer.

Optionally, embedding of the pharmaceutical occurs before (e.g. mixingpharmaceutical particles into fibers of porous structure at fibercreation), during (e.g. using the dipping method of FIG. 19) and/orafter (e.g. a spray on pharmaceutical after apparatus is made) themanufacture of enhanced stent apparatus 100. In some exemplaryembodiments of the invention, a pharmaceutically embedded porousstructure 104 is placed on top of a pharmaceutically treated supportelement 102. In some exemplary embodiments of the invention, porousstructure 104 is coated with at least a polymer. In some exemplaryembodiments of the invention, a porous structure is provided with apolymer coating which contains a pharmaceutical which elutes from thecoating.

Pharmaceuticals are optionally embedded into porous structure 104 suchthat they are released into the patient over an approximatepredetermined amount of time. For example, pharmaceuticals areoptionally embedded into porous structure 104 for release over thecourse of a week. Other pharmaceuticals are optionally embedded intoporous structure 104 for release over the course of months. Factorswhich vary according to the release schedule of the pharmaceuticalinclude the type of material used to construct porous structure 104, thetype of pharmaceutical being used, the manner in which porous structure104 is constructed, and/or the amount of coverage of support element 102that porous structure 104 provides.

In some exemplary embodiments of the invention, 1 microgram ofpharmaceutical per square centimeter of fiber surface coverage (not thearea of the fiber themselves, but the area of the tissue it treats) areais embedded on the fibers. Optionally, up to 200 micrograms ofpharmaceutical per square centimeter of fiber surface area is embeddedon the fibers. Optionally, a higher or lower concentration ofpharmaceutical is used depending on the therapeutic needs of the patientand depending on the type of drug used.

Large and/or Complicated Stereochemistry Molecule Pharmaceutical Usage

In some exemplary embodiments of the invention, usage of porousstructure 104 for enhanced pharmaceutical delivery allows for effectivedispersion and delivery of large molecule and complex stereochemistrypharmaceuticals. Traditionally, large molecule pharmaceuticals are notused with drug eluting stents because they don't diffuse very well andthe widely spaced struts of traditional stents do not facilitate evenand/or widespread diffusion of the large molecule, as described above.In contrast, use of a device with more extensive coverage of a vascularwall would make treatment using large molecule pharmaceuticals morefeasible. This is optionally accomplished by providing porous structure104 and/or support element 102 with large molecule pharmaceuticals forelution and taking advantage of the increased vascular wall coverage ofporous structure 104, due to the smaller aperture sizes in someexemplary embodiments. Alternatively or additionally, due to theovergrowth of porous structure 104 by cells from the body, largemolecule pharmaceuticals are more efficiently delivered to the patientas pharmaceuticals are delivered into tissue, rather than being washedaway in the blood stream, for example. Optionally, pharmaceuticalslarger than 700 Dalton, 1,000 Dalton, 3,000 Dalton or up to 50,000Dalton are dispersed and delivered evenly into patient's vasculature.

Optionally, liposomes are eluted from at least one porous structure 104and/or support element 102. Optionally, steroids, statins,anticoagulants, gemcitabine (Gemzar®), zolimus or zotarolimus(ABT-578®), sirolimus (e.g. Rapamycin®), taxol/paclitaxel, and/or otherlarge or complex molecule pharmaceuticals are eluted from at least oneporous structure 104 and/or support element 102. Referring to FIG. 3,pharmaceutical agents 406 are shown eluting from enhanced stentapparatus 100 into artery 400 from lumen wall 404. Optionally, agents406 elute from porous structure after at least some growth ofendothelial cells 408 through enhanced stent apparatus 100, for examplethe time determined by experimental endothelial cell growth data. Asdescribed elsewhere herein, porous structure 104 optionally acts to trapdebris 402 between the exterior surface of enhanced stent apparatus 100and lumen wall 404.

Timed Release Pharmaceutical Usage

In an exemplary embodiment of the invention, pharmaceuticals are elutedfrom an enhanced stent apparatus into overgrown endothelial tissue andnot merely into the interior surface of the lumen being treated. In anexemplary embodiment of the invention, pharmaceutical release is thusoptimized by ensuring that only a pre-defined amount of drug is lostinto the bloodstream and/or into other non-therapeutic media. In someexemplary embodiments, including, for example, in conjunction with BBBtreatment as described below, endothelial cell growth can assist withpharmaceutical therapy by providing a transfer medium for thepharmaceutical from an implanted stent to the body area being treated.

In some exemplary embodiments of the invention, pharmaceuticals areeluted depending on the extent of endothelial tissue growth. Optionally,pharmacological treatment commences after some endothelial cell growthis exhibited through and/or around the enhanced stent apparatus.Optionally, pharmacological treatment begins upon implantation withoutregard to endothelial cell growth. In some exemplary embodiments of theinvention, the enhanced stent apparatus is adapted and constructed totime-release pharmaceuticals in accordance with a predeterminedtreatment schedule. Optionally, the predetermined treatment scheduleaccommodates anticipated and/or actual endothelial cell growth rates byutilizing a coating with a predetermined breakdown rate. Optionally,release of pharmaceuticals is determined by time in situ. For example,if it is estimated that it would take 8 hours for endothelial cellgrowth to completely encapsulate the implanted stent, pharmaceuticalslocated in the porous structure of the stent optionally have apredetermined 8 hour delay prior to release and/or elute at a low rateto prevent inefficient or undesirable (i.e. toxic overdose) use of thepharmaceutical. In an embodiment of the invention, it takes only fewhours for the endothelial cells to cover the thin porous structure,therefore the time release delay is adapted to match. This may beachieved by coating porous structure 104 with a “diffusion barrier”layer that to inhibits the diffusion of drug for a predefined period.Optionally this may be achieved by using a controlled degradable matrix.Optionally, pharmaceutical release occurs after only partial growth ofendothelial cells around and/or through porous structure and/or stent.Optionally, pharmaceuticals begin to elute immediately upon insertionand/or implantation into a body lumen. Optionally, it is sufficient forpharmaceutical therapy that porous structure 104 has any biologicalcovering, such as mucus, etc. In some embodiments of the invention,delay is determined according to the material that is expected toovergrow porous structure 104.

In an exemplary embodiment of the invention, timed release ofpharmaceuticals is accomplished by coating and/or constructing porousstructure 104 and/or support element 102 of multiplebiodegradable/resorbable layers. By using layers which offer differentperformance characteristics (e.g. different pharmaceutical, differentdegradation time, stickiness to the body lumen, surface treatmentmodifications (e.g. treatment to make it non-sticky to the lumen)),enhanced stent apparatus 100 can be tailored to perform a specifictreatment schedule. For example, layer #1 (the external layer) iscomprised of a material which degrades in 2 hours, layer #2 (an innerlayer) includes a pharmaceutical for elution into the patient and whichdegrades in 10 hours minutes, layer #3 (an inner layer) includes adifferent pharmaceutical for elution into the patient which degrades in6 hours, and so on. Naturally, depending on the therapy desired for thepatient, the layers and/or performance characteristics of those layersare changed to provide the desired treatment. It should be noted that abiodegradable layer can be placed in the outermost position which istimed to the expected endothelial cell growth, as described above. Insuch an embodiment, the degradation of the outermost layer is completedat approximately the same time as the completion of the endothelial celllayer overgrowth of enhanced stent apparatus 100, enabling apharmaceutical to be eluted directly into endothelial tissue from asecond layer of enhanced stent apparatus 100.

In an exemplary embodiment of the invention, support element 102 elutespharmaceuticals, but treatment is assisted by porous structure 104 whichencourages endothelial cell growth over support element 102. Optionally,the pharmaceutical located on support element 102 elutes slowly to allowfor endothelial cell growth. In some embodiments of the invention, therate of elution depends on the local concentration and the anticipateddiffusion rate of the pharmaceutical through the surrounding bodytissue.

In some embodiment of the invention, a first pharmaceutical agent iseluted, which is designed to encourage endothelial cell overgrowth,followed by a second pharmaceutical agent designed to treat a malady ofthe patient.

In some embodiments of the invention, at least porous structure 104 isattached to the lumen using an adhesive which is impermeable to thepharmaceutical in porous structure 104. However, timed release isachieved by allowing the endothelial layer to overgrow porous structure104, such that the pharmaceutical will elute into the endothelial layerthat is not proximal to the adhesive. Optionally, the adhesive isbiodegradable and/or bioresorbable and merely delays elution.

Blood Brain Barrier (BBB) Therapy

The BBB is the specialized system of capillary endothelial cells thatprotects the brain from harmful substances in the blood stream, whilesupplying the brain with the required nutrients for proper function.Unlike peripheral capillaries that allow relatively free exchange ofsubstance across/between cells, the BBB strictly limits transport intothe brain through both physical (tight junctions) and metabolic (enzyme)barriers. Thus the BBB is often the rate-limiting factor in determiningpermeation of therapeutic drugs into the brain.

In some exemplary embodiments of the invention, a pharmaceutical elutingporous structure is used to enable treatments through the BBB. Asdescribed herein, pharmaceutical therapy is often enhanced byendothelial cell growth through and/or around an implanted drug elutingstent. Use of porous structure 104 in brain arteries, allows theendothelium cells to grow over the porous structure 104, thus embeddingporous structure 104 into the arterial tissue. The end result, after theprevious endothelial cell layer has been absorbed by the body is thatporous structure 104, which contains a brain treating pharmaceutical, ison the other side of the endothelium layer, thus on the other side ofthe BBB, with no significant impediment between porous structure 104 andthe brain tissue. In addition, some exemplary embodiments of porousstructure 104 are suitably sized to be used in the narrow lumens foundin the brain. Exemplary pharmaceuticals suitable for use with porousstructure 104 in treating through the BBB include gemcitabine (Gemzar®),and enzastamin, dopamine and dopamine derivatives, and anti-cancerdrugs. In some embodiments of the invention, porous structure 104 elutesanti-BBB materials for lowering resistance to transmission of substancesthrough the BBB.

Pharmaceutical Treatment of Small Lumens

Currently, small lumens such as small coronary or brain arteries aretreated only with a balloon type catheter. These treatments are shortterm and do not lend themselves to rendering pharmaceutical treatment tothe lumen, as is sometimes desired. Traditional stenting is not oftenperformed at the very least due to the difficulty of navigating a stentinto the small spaces of these arteries. In an exemplary embodiment ofthe invention, lumens smaller than 2 mm in diameter are treated withpharmaceuticals using at least a pharmaceutical eluting porous structure104, and optionally a support element. Optionally, the support elementis a stent. Optionally, the support element is a balloon on which porousstructure 104 is placed. In an exemplary embodiment of the invention, aballoon-type catheter is used to insert porous structure 104 in a smalllumen. The balloon is expanded to cause porous structure 104 expansionand to instigate contact between porous structure 104 and the lumen wallto be treated. In an embodiment of the invention, porous structure 104at least partially adheres to the lumen wall. Optionally, abiocompatible adhesive is used to adhere porous structure 104 to thelumen wall. In some embodiments of the invention, porous structure 104is self-expandable and does not need, or only partially relies on theballoon for expansion. In an embodiment of the invention, the balloon isremoved once porous structure has been deployed within the small lumen.

In some embodiments of the invention, small lumens are treated longterm, which is not performed currently. For example, by implanting atleast the porous structure of an enhanced stent apparatus 100, treatmentcan last on the order of months (e.g. a month or more). Optionally,treatment can last on the order of weeks (e.g. a week or more).

Exemplary Treatment Methods

In an exemplary embodiment of the invention, enhanced stent apparatus100 is used for treating, dilating, drugging and/or supporting bodylumens, such as blood vessels. In some exemplary embodiments of theinvention, enhanced stent apparatus 100 is used for treatment ofdisorders in the carotid arteries. In some embodiments of the invention,enhanced stent apparatus 100 is used for treatment of disorders in thecoronary arteries. As described above, treatment can be rendered throughthe BBB. Stent apparatus 100 can be either a balloon expandable stent ora self-expandable stent, or use any other expansion method. Optionally,support element 102 and/or porous structure 104 are self-expandable.Optionally, pharmaceuticals are used to treat a patient via body lumens,for example, as described herein. In some embodiments of the invention,enhanced stent apparatus 100 is used for treatment of aneurisms(described below), for example in the brain. In some embodiments of theinvention, enhanced stent apparatus 100 is used for preventativetreatment of vulnerable plaque.

In operation, enhanced stent apparatus 100 is navigated to the area in abody lumen 400, as shown in FIG. 3, where the enhanced stent apparatus100 is to be emplaced, using techniques known in the art. In someexemplary embodiments of the invention, enhanced stent apparatus 100 canbe expanded within body lumen 400 using a balloon. Optionally, enhancedstent apparatus 100 can be expanded within body lumen 400 usingself-expandable techniques known in the art. Optionally, support element102 and/or porous structure 104 are constructed of a thermo-sensitive,shape memory alloy which, when exposed to a patient's natural bodytemperature, assumes an expanded shape within body lumen 400 at sometime after situation in the appropriate location to render treatment.Alternatively, super-elastic or elastic release is used for placing astent in a treatment area. In some exemplary embodiments of theinvention, a balloon is used to pre-dilate body lumen 400 at a treatmentarea prior to implantation of enhanced stent apparatus 100 at that area,in an at least a two step (1. pre-dilate, 2. implant apparatus 100)procedure. Optionally, only porous structure 104 is implanted and notthe whole enhanced stent apparatus 100. In some exemplary embodiments ofthe invention, a balloon is used to post-dilate body lumen 400 at atreatment area after implantation of enhanced stent apparatus 100 atthat area, in an at least a two step (1. implant apparatus 100, 2.post-dilate) procedure. This kind of procedure is commonly used whenimplant apparatus 100 is a self-expandable stent, such as for carotidapplications.

In some exemplary embodiments of the invention, the porous structuremesh is filled with a material which improves the stiffness of theporous structure temporarily until it arrives at a treatment site in alumen. In some embodiments of the invention, the material is dissolvedby naturally occurring substances in the body, such as enzymes.Optionally, the dissolving is timed to the anticipated overgrowth ofporous structure 104 by the endothelial cell layer. Optionally thematerial is fibrogane. Optionally, the material is albumin fibroganehelonic acid laminin.

Exemplary Treatment of Embolic Showers at Insertion and/or Deployment

It is commonplace in stenting procedures to use an embolic showerprotection device which is situated only during the stenting proceduredownstream from the treatment area, the idea being that the protectiondevice will trap debris which falls from the blood vessel walls duringthe stenting procedure. In an exemplary embodiment of the invention,usage of enhanced stent apparatus 100 with porous structure 104 obviatesthe need for an embolic shower protection device. The small aperturesize of porous structure 104 is designed to trap arterial wall plaque402 and other debris of a particular size that becomes dislodged duringand/or after the stenting procedure, between porous structure 104 andthe lumen wall 404. In an exemplary embodiment of the invention, debrisgreater than the size of the apertures in diameter is prevented fromentering the bloodstream in this manner.

An additional advantage of using implanted porous structure 104 insteadof a conventional embolic shower protection device is that it remains inplace after the procedure. That is, debris which becomes dislodged atsome time after the stenting is performed still becomes trapped byporous structure 104. This is an improvement over the embolic showerprotection device conventionally used, which is removed at theconclusion of the stenting procedure. Optionally, enhanced stentapparatus 100 is used with an embolic shower protection device asreassurance during the stenting procedure. Optionally, porous structure104 filters a particular type or types of debris while support element102 filters another type or types.

It should be noted further that in an exemplary embodiment of theinvention the aperture sizes of the porous structure 104 are designedand constructed to permit the passage of blood therethrough. Thisprevents the “jailing” of branching blood vessels which prevents thepassage of critical blood components, such as red blood cells frompassing into the branching vessel. In an exemplary embodiment of theinvention, the aperture size of porous structure 104 is larger than theaverage size of a red blood cell, or about 7 microns, allowingthroughput of red blood cells without the risk of producing significanthemolysis. In some exemplary embodiments of the invention, theapproximate aperture diameters are greater than 20 microns. In someexemplary embodiments of the invention, the approximate aperturediameters are smaller than 100 microns thus allowing blood to flowthrough while holding large debris (>100 microns) in place.

Carotid stenting is rarely performed currently, due to the high risk ofdebris becoming dislodged during the stenting procedure. This dislodgeddebris then travels to the brain where it often causes serious injury tothe patient. In order to combat this problem of dislodged debris,enhanced stent apparatus 100, which includes porous structure 104, isused for stenting in the carotid arteries in some exemplary embodimentsof the invention.

Exemplary Treatment of Aneurisms

Referring to FIG. 20A, a typical aneurism volume 2002 is depictedpromulgating from a body lumen 2004. FIG. 20B shows a current method oftreating an aneurism called coil embolization. Coil embolization isparticularly indicated for treatment of cerebral aneurisms. Coilembolization of cerebral aneurisms involves the insertion of a catheterthrough the groin with a small microcatheter navigated to the aneurismitself through the cerebral arteries. A coil 2006 is then deployed intothe aneurism filling it from within and thus disturbing the blood flowin the aneurism volume. This effect that leads to the creation of bloodclot, which is trapped in aneurism volume 2002 and which eventuallyturns into a more solid structure, thus reducing the risk of rupture ofthe aneurism. In some treatments, a stent 2008 is also used in order tokeep coil 2006 from falling out of aneurism volume 2002 and into theblood stream. However, in some cases parts of coil 2006 protrude throughstent 2008 and are therefore exposed to the blood flow within the lumen2004. Additionally, safe insertion of coil 2006 into aneurism volume2002 can be a complicated procedure. Additionally, the blood clotproduced might grow through the stent struts into the blood vessellumen, narrowing it possibly to the point of complete occlusion.

Referring to FIG. 20C, an embodiment of the invention is shown in whichporous structure 104 located on enhanced stent apparatus 100 is used totreat an aneurism while preventing coil 2006 from protruding into lumen2004. Optionally, a cerebral aneurism is treated by this method. Porousstructure 104 is adapted to have aperture sizes which are small enoughto prevent coil 2006 from protruding into lumen 2004, in accordance withan embodiment of the invention. Optionally, a to plurality of porousstructures are used at least slightly out of phase in order to preventat least a portion of coil 2006 from protruding into lumen 2004. In someexemplary embodiments of the invention, coil 2006 is covered with aporous structure (separate from porous structure 104), thereby creatingmore surface area for the blood to stick to, enhancing the creation of ablood clot within the aneurism volume 2002. In some embodiments of theinvention, porous structure 104 is manufactured using an electrospinningtechnique.

In an exemplary embodiment of the invention, enhanced stent apparatus100 is used to treat an aneurism without the need for coil 2006. In someembodiments of the invention, porous structure 104 is adapted torestrict blood flow into aneurism volume 2002, thus causing the trappedblood in aneurism volume 2002 to clot, which in time will solidify andcreate a solid tissue structure thus reducing the likelihood of aneurismrupture or expansion as a result of increased blood flow thereto. Forexample, the aperture sizes in porous structure 104 may be small orspaced widely apart. Optionally, a plurality of “out of phase” porousstructures are used together to restrict blood flow into aneurism volume2002. Optionally, porous structure 104 has apertures smaller than 20microns. Eliminating the need of coil 2006 is advantageous, as it makesthe procedure faster, safer, and simplifies the delivery catheter thatcan be used to perform the procedure.

In some exemplary embodiments of the invention, porous structure 104 isshorter than support element 102. A shorter porous structure 104 isoptionally used so that only the aneurism is treated and not a healthyportion of the lumen. Optionally, a shorter porous structure 104 is usedto avoid restricting blood flow to a branching vessel. Optionally,porous structure 104 has small aperture sizes on the aneurism side forrestricting flow therethrough, while the other side has larger aperturesto avoid restricting blood flow to a branching vessel.

In some exemplary embodiments of the invention, porous structure 104 iscomprised of a self-expanding material, such as nitinol, having enoughradial force to hold itself in place within the lumen. Optionally, asupport element 102 is not used at all and porous structure 104 providesthe necessary treatment to the aneurism. Optionally, the radial pressureapplied by porous structure 104 is equivalent to about 1 atmosphere.Optionally, the aperture diameters for aneurism treatments are smallerthan 30 microns.

In some embodiments of the invention, porous structure 104 also preventsblood clots and/or other embolism-causing debris from entering the lumen2004 from aneurism volume 2002.

Exemplary Treatment of Vulnerable Plaque

Identification of vulnerable plaque areas allows prophylactic treatmentof these areas before they can create problems for the patient. In anembodiment of the invention, an enhanced stent apparatus 100 is used topreemptively treat lumen areas expected to trigger problematicconditions for the patient in the future. For example, plaque oftenbuilds up in blood vessels which in some cases breaks off in a clump orpartially tears, causing a thrombosis. The downstream movement of theplaque or thrombosis is a potential cause of a heart attack, stroke orother malady in the patient. In some embodiments of the invention, anenhanced stent apparatus, including at least porous structure 104 isimplanted at a potentially problematic location within a lumen,preventing the plaque from rupturing and, thus, from entering thebloodstream. In some embodiments of the invention, porous structure 104elutes at least one pharmaceutical used for treating the conditionaffecting the lumen, such as those described herein. In some embodimentsof the invention, porous structure 104 is made of nitinol as aself-expandable stent, having enough radial force to hold itself inplace, without the supportive element 102.

Exemplary Method of Implantation

In some exemplary embodiments of the invention, porous structure 104 ispositioned on a catheter, such as an expandable balloon, forimplantation in a lumen separately from or without support element 102.Treatment with a catheter is optionally provided by using the catheterto implant porous structure 104 adapted and constructed for renderingtreatment to a lumen over time. Optionally, pharmaceuticals or othertherapeutic agents are embedded within porous structure 104, such asdescribed herein. Positioning, in an exemplary embodiment of theinvention, entails inserting the catheter at least partially through theinterior of porous structure 104 along central axis 106. In someembodiments of the invention, a balloon is deflated prior to positioningof porous structure 104 thereon. Optionally, the balloon is at leastpartially inflated prior to positioning of porous structure 104 thereonand then deflated and/or folded prior to insertion into the patient.

During delivery of porous structure 104 to a treatment site within alumen, a balance is optionally struck between securing porous structure104 to the catheter during delivery, but not so securely as to preventimplantation of porous structure 104 at the treatment site, and allowingdeflation of a balloon and/or pulling the catheter out while leaving theporous structure 104 inside the lumen intact. For example, porousstructure 104 is optionally adhered to catheter at selected points usingan adhesive such as loctite instant adhesive number 40340, 40840, 46040or 3411-UV curable. The adhesive is strong enough to prevent porousstructure 104 from slipping off the catheter during delivery, howeverupon self-expansion or expansion of balloon the bonds between porousstructure 104 and the catheter are broken, allowing for implantation ofporous structure 104 at a treatment site within a lumen. In someembodiments of the invention, delivery lasts for 6 hours or less.Optionally, delivery lasts for 3 hours or less. Optionally, deliverylasts for 1 hour or less.

In some exemplary embodiments of the invention, the catheter is treatedwith an anti-sticking agent such as Parylene-c, silicon coating and/orTeflon® (PTFE) coating, to help prevent porous structure 104 fromstaying fastened to catheter after deployment at treatment site.Optionally, a thin film is coated onto the catheter which secures porousstructure 104 to the catheter during the delivery, but dissolves upon anapproximate lapsing of time, allowing porous structure 104 to be removedfrom the catheter. Optionally, the thin film is comprised of albuminfibrogane helonic acid laminin. Optionally, the thin film layer is up toa few microns thick. Alternatively, the thin film layer is 0.1 micronsin thickness.

In some exemplary embodiments of the invention, the mesh-like structureof porous structure 104 is filled and/or encapsulated with a gel typematerial, such as fibrogane, fibrinogen and/or hyaluronic acid and/orlaminin. The gel material stiffens porous structure 104 for delivery,however, upon extended exposure to intra-lumen conditions, the geldissolves leaving only porous structure 104 after some period of time,for example a few hours or days.

In an embodiment of the invention, an adhesive material which issensitive to a certain threshold (e.g. 1 atm. up to 20 atm.) of pressureis placed on porous structure 104 such that when the balloon pressuresporous structure 104 against the lumen, porous structure 104 adheres tothe lumen. In an exemplary embodiment of the invention, when porousstructure 104 is coated with the pressure sensitive adhesive it is onlycoated on the lumen side of porous structure 104. Optionally, porousstructure 104 is covered with a selectively adhesive material which hasa high affinity for adhering to body tissue, for example fibrin sealant,biological glue, collagen, hydrogel, hydrocolloid, or collagen algirate,but limited affinity for adhesion to other substances, such as adelivery catheter or balloon.

Upon arrival at a lumen treatment site, the balloon is expanded in orderto place porous structure 104, in accordance with an exemplaryembodiment of the invention. As described above, porous structure 104 isoptionally placed on the balloon such that when the balloon is expanded,porous structure 104 is expanded correspondingly. In some exemplaryembodiments of the invention, the balloon is expanded until it begins toapply pressure to the internal surface of the lumen being treated. Theamount of pressure exerted by the balloon is variable depending on thepurpose and technique used to carry out the treatment. In some exemplaryembodiments of the invention, the balloon is expanded to press porousstructure 104 against an interior surface of the lumen being treated.Optionally, the expansion pressure is used to overcome a stenosis beingtreated. Optionally, porous structure 104 is at least temporarilyfastened to the interior surface of the lumen with the assistance of anadhesive. In some exemplary embodiments of the invention, porousstructure 104 is at least temporarily attached using at least one barbor pin located on an exterior surface of porous structure 104 facing theinside surface of the blood vessel. Optionally, the adhesive is appliedto the exterior surfaces of porous structure 104 prior to insertion intothe lumen. In some exemplary embodiments of the invention, once porousstructure 104 is placed at the treatment site within the lumen, asupport element 102 is implanted at the same site interior of porousstructure 104 in relation to the interior surface of the lumen, thussandwiching porous structure 104 between support element 102 and thelumen.

In some exemplary embodiments of the invention, porous structure 104provides mechanical support to a blood vessel wall. Optionally, porousstructure 104 support is in addition to support rendered by supportelement 102. Alternatively, porous structure support 104 is in lieu ofsupport rendered by support element 102. In some exemplary embodimentsof the invention, support element 102 provides no or minimal support tothe blood vessel wall while supporting porous structure 104. Optionally,porous structure 104 provides pharmacological treatment to blood vesselwhile providing no or minimal support to blood vessel. Optionally,porous structure 104 is implanted along with support element 102,however support element 102 degrades in situ, leaving porous structure104. Optionally, porous structure 104 prevents support structure 102from falling apart in large pieces, permitting release of piece ofsupport structure 102 only when below a certain threshold size, forexample under 20 microns in diameter. Optionally, porous structure 104is implanted along with support element 102, however porous structure102 degrades in situ, leaving support element 102. This lastconfiguration is sometimes indicated when porous structure 104 is madeof a polymer containing a pharmaceutical. Eliminating the polymer andthe pharmaceutical after period of time has an advantage because itreduces the likelihood of long term side effects such as thrombosisassociated with the presence of the polymer and the pharmaceutical.

Stent assemblies, with or without jackets, are used in opening vessellumens in a variety of vascular tissue including, inter alia, stenoticcoronary arteries, stenotic carotid arteries and stenotic organvasculature.

Prior Art Stent and Jacket Configurations

Referring to FIG. 24 a, a stent assembly 100 comprises a stand-alonetubular stent 202, without a jacket, herein bare stent 202. Bare stent202 typically comprises a metal or polymer tubular structure havinglarge, mesh-like, apertures 270. Bare stent 202 is shown encircling aballoon 260 and, upon expansion of balloon 260, bare stent 202 expandsradially outward.

As seen in FIG. 24 b, bare stent 202 has expanded radially in vessellumen 125 to press against a stenotic area of tissue 240, therebycompressing and cracking stenotic area 240 radially outward. Followingdeployment of stent assembly 100, vessel lumen 125 expands, allowingbetter circulation through lumen 125.

Deployment of bare stent 202, however, causes damage to a basalaminaintimal layer 127 resulting in the formation of scars 242, plaques 244and new stenotic lesions 240 that protrude through apertures 270. Overthe long-term, a large percentage of the recipients of bare stents 202will develop significant stenotic lesions 240 that block vessel lumen125, causing what is known as restenosis.

To prevent restenosis, (FIG. 24 c), stent assemblies 200 have beendeveloped comprising stents 202 with an internal or external jacket 204having small apertures. Stent assembly 200 is shown in position around aspindle holder 180, emerging from a compression sheath 182, with stent202 and stent jacket 204 in substantial tubular alignment. Typically,the jacket is formed of a polymer.

During expansion, jacket 204 prevents embolitic debris 121 generatedfrom plaques along basalamina intimal layer 127 from entering vessellumen 125.

In FIG. 24 d, stent assembly 200 is expanded radially in vessel lumen125 so that jacket 204 presses stenotic tissue 240 radially outward.Following deployment of the stent assembly 200, stent jacketsubstantially prevents scars 242, plaques 244 and stenotic lesions 240from protruding through apertures 270. In spite of substantiallypreventing restenosis, stent jacket 204 creates its own set of problemsrelated to formation of an embolism 300.

As noted above, to provide sufficient strength, stent jacket 204 may bemade of interlacing knitted fibers, and/or fibers subject to chemical orheat treatments, all of which tend to increase the thickness of fibers210 and bulk of jacket 204, seen in FIG. 25.

Within 48 hours following implantation of stent assembly 200 a layer ofendothelial cells 220 coat stent jacket fibers 210 and basalaminaintimal layer 127, as seen in FIG. 25.

Endothelial cells 220 have a diameter 222 of approximately 20micrometers and maintain adherence to basalamina intimal layer 127 butgenerally do not substantially adhere to jacket fibers 210.

Fibers 210 in stent jacket typically have a thickness 212 of 20micrometers so that endothelial cell 220 that straddles fiber 210, willhave no attachment to basalamina intimal layer 127 and will easilydislodge from fiber 210.

Additionally, fibers 210 are typically spaced a distance 218 of lessthan 20 micrometers so that endothelial cell 220 that straddles betweentwo fibers 210, will attach to the two adjacent fibers 210 and will havea marginal attachment to basalamina intimal layer 127 therebetween;again resulting in a cell 220 that is easily dislodged from fibers 210.

Single endothelial cells 220 that become detached from basalaminaintimal layer 127, are not large enough to be recognized by platelets asforeign bodies around which to aggregate. However, as seen in FIG. 26,during natural movement of fibers 210, for example during regularpulsation of blood in circulation, a release of multiple interconnectedcells 220 occurs.

In this case four endothelial cells 220, have broken loose frombasalamina intimal layer 127, and are freely floating in vessel lumen. Aplatelet 310, having a diameter 320 of between four to ten times thediameter of endothelial cells 220, is attracted to masses that compriseat least two endothelia cells 220 and endothelial cells 220 provide anexcellent attractive target for platelet 310.

As seen in FIG. 27, a single platelet 310 has adhered to dislodgedendothelial cells 220. As seen in FIG. 28, as a result of chemotaxis,additional platelets 310 have aggregated around endothelial cells 220 toform an embolism 300.

As noted above, embolism 300, comprising aggregated platelets 310,presents a health threat that can form at any time followingimplantation of stent jacket 204 causing an estimated 2% of allrecipients of jacketed stents 204 to eventually develop necrosis ofvital organs and/or die.

The tremendous and constant threat of emboli 300 from stent-and-jacketassembly 204 (FIG. 26) has resulted in lifetime administration ofplatelet aggregation reduction APIs. There are many life-threateningsequelae associated with Clopidogrel and there are many clinical trialsbeing conducted on alternative platelet aggregation reducing APIs,including: Ticlopidine, Cangrelor, ARMYDA-2, and Prasugrel.

(Journal of Interventional Cardiology “TCT Annual Meeting: AntiplateletAgents”; Volume 19 Page 193—April 2006.)

As noted above, lifetime administration of platelet aggregation reducingAPIs, herein Clopidogrel, present problems to many sectors of thepopulation.

For example, many jacketed stent recipients develop reactions thatrequire cessation of Clopidogrel, such reactions include: ulcers, skinrashes, and syncope. With high bulk jacketed stents, Cessation ofClopidogrel puts the patient at risk for developing a life threateningembolus 300.

In addition to the hazards of embolus 300, there are patients who, notonly must cease taking Clopidogrel and its accompanying risks, but mayalso develop conditions that are life threatening of themselves,including myelotoxicity, acquired hemophilia and TTP.

Additionally, there are the conditions that the patient may have thatprevent the administration of Clopidogrel, including unresponsiveness toa platelet aggregate reducing API, an antithrombin deficiency,hereditary antithrombin deficiency (HD), immune depression, low CCR5Delta 32 homozygous genotype (CCR5), acquired hemophilia, AIDS, HIV.

Moreover, there are risks presented to virtually every person receivinga jacketed stent. To prevent excessive bleeding in conjunction withvirtually any surgery, Clopidogrel administration must be ceased for asignificant period of time both pre-operatively and post-operatively. Asa result, a patient who has received a stent and is a candidate for anelective surgery, for example prostate removal, is presented with aHobson's choice of ceasing Clopidogrel administration and risking deathfrom emboli, or taking Clopidogrel and risking embolism-free bleeding,hemorrhage and death.

Optimized Stent Assemblies

It has been found that specific configurations of the above-noted stentsand jackets appear to provide advantages as is explained in the“Experimental Data” section. The specific features of theseconfigurations will now be addressed.

Single fiber knits have been used in pantyhose since 1939, and comprisea plurality of interconnected loops known for strength, elasticqualities and thinness. Single fiber knit fabrics would be desirable aslow bulk jackets 600 were it not from the problem that any loop alongthe edge of the nylon material can flip 180 degrees and form a run.

FIG. 29 shows a knitted stent jacket 600 comprising knitted fibers 620forming apertures 110. To prevent flipping in fibers 620, an elastomericbelt 640 has been passed through apertures 110 at the distal end ofstent jacket 600. Optionally, an elastomeric belt 640 is similarlypassed through loops at the proximal end of stent jacket 600 (notshown).

As used herein, any reference to a “knitted material” includes anymaterial that is manufactured by a knitting process, including, interalia: a material knitted from a single fiber, comprising eithermonofilament or multifilament fiber. The single fiber may comprise,inter alia, polyethylene, polyvinyl chloride, polyurethane, nylon,stainless steel, nitinol, or any other metal.

The biostable polymer comprises, inter alia, any one of a polyolefin, apolyurethane, a fluorinated polyolefin, a chlorinated polyolefin, apolyamide, an acrylate polymer, an acrylamide polymer, a vinyl polymer,a polyacetal, a polycarbonate, a polyether, an aromatic polyester, apolyether (ether keto), a polysulfone, a silicone rubber, a thermoset,and a polyester (ester imide).

The natural polymer comprises, inter alia, a polyolefin, a polyurethane,a Mylar, a silicone, a polyester and a fluorinated polyolefin.

As seen in FIG. 30, knitted stent jacket 104 includes apertures 110 thatare maximized so that fibers 620 provide a small total coverage area inwhich stent jacket 104 covers a stent 102.

In accordance with some embodiments of the present invention, in anexpanded state, the area of aperture 110 is between about 50,000 squaremicrometers and about 70,000 square micrometers. In alternativeembodiments, aperture 110 has an area of between about 40,000 squaremicrometers and about 60,000 square micrometers. In other embodiments,aperture 110 has an area of between about 30,000 square micrometers andabout 50,000 square micrometers.

With knitted stent jacket 104 having fibers 620 presenting a small totalcoverage, crimping stent 102 for insertion into compression sheath, 182(FIG. 24 c) for example, is relatively simple.

Additionally, a small total coverage allows crimped stent 102 to have asmall profile, allowing easy maneuverability through lumen 125.

Moreover, with knitted stent jacket 104 having minimal thickness offibers 620, stent jacket 104 substantially has a minimal influence onthe mechanical properties of the stent during the delivery andexpansion.

The location of jacket 104 externally on stent 102 protects basalaminaintimal layer 127 from damage during expansion of stent 102.Additionally, the location of jacket 104 externally on stent 102provides substantial protection against debris 121, seen in FIG. 24 d,entering vessel lumen 125 during expansion of stent 102.

In accordance with some embodiments of the present invention, a proximalportion of jacket 104 is attached to a proximal aspect of stent 102using a process selected from the group consisting of: sewing, adhesion,gluing, folding, suturing, riveting and welding. Such an attachment, forexample, allows stent 102 to expand with a typically differentcoefficient of expansion than that of jacket 104 without causing damageto basalamina intimal layer 127.

As seen in a plan view of knitted stent jacket 600 in FIG. 30, knittedstent jacket 104 comprises a small coverage area noted in Appendix I,for example about 9%, or about 10%, or about 11%, or about 12% of thesurface area of associated self-expanding stent 102. In general, thecoverage area is less than 16%. Hence, in spite of crimping stent 102prior to deployment, there is no need to fold knitted jacket 104 to fitinto sheath 182 (FIG. 24 c) prior to deployment; thereby reducing bulkand increasing maneuverability of stent assembly 200.

Chart 1 the attached Appendix provides support that the above-notedparameters of a knitted jacket on a self-expanding stent can be easilyattained in the present invention using a fiber diameter of about 12.5micrometers.

FIG. 31 shows details of knitted jacket 600 in which apertures 110 havea longitudinal length 650 of greater than about 160 micrometers. Inother embodiments, longitudinal length 650 is greater than about 180micrometers. In other embodiments, longitudinal length 650 is greaterthan about 200 micrometers.

In accordance with some embodiments of the present invention, apertures110 have a transverse length 642 of greater than about 250 micrometers.In other embodiments, transverse length 642 is greater than about 240micrometers. In other embodiments, transverse length 642 is greater thanabout 230 micrometers.

It will be appreciated that the shorter one of the longitudinal length650 and the transverse length 642 defines the minimum center dimension630 (D) which must be greater than about 230 micrometers, andpreferably, greater than 240 micrometers, and still more preferably,greater than 250 micrometers.

FIG. 32 shows that fibers 620 have a diameter 662, optionally in a rangeof between about 7 micrometers and about 18 micrometers. In otherembodiments, diameter 662 is in a range of between about 10 micrometersand about 15 micrometers. In still other embodiments, diameter 662 is ina range of between about 11 micrometers and about 14 micrometers. Instill other embodiments, diameter 662 is in a range of between about 12micrometers and about 13 micrometers. In still other embodiments,diameter 662 is in a range of between about 12.25 micrometers and about12.75 micrometers. In still other embodiments, diameter 662 of about12.5 micrometers.

Substantially inherent advantages of the measurements of knitted jacket600 become readily apparent in FIG. 33 in which endothelial cells 220are well adhered and stable against basalamina intimal layer 127 due tothe thinness of fibers 620.

As a result of such spacing, a typical endothelial cell 220 will havesubstantial contact with basalamina intimal layer 127 as endothelialcell 220 is prevented from adhering to more than one column of fibers620 due to the distance therebetween.

A group of three endothelial cells 220 is seen adhering to a portion ofknitted stent jacket 600. Endothelial cells 220 have an amoeba-likemovement so that at a fiber junction 692, cell 220 will typically touchdown on junction 692 and move until a substantial portion of cell 220 isin substantial contact with basalamina intimal layer 127. In rare caseswhere a cell 228 fails to properly anchor into basalamina intimal layer127, that specific single cell 228, alone, may have a tendency todislodge due to movement of fibers 620 during normal pulsation in theblood circulation cycle. Due to the stability of adjacent cells 220resulting from substantial contact with basalamina intimal layer 127,multiple cells 220 will not dislodge together with single cell 228.

As shown, single endothelial cell 228 has separated from basalaminaintimal layer 127. However, single cell 228 does not have the necessarymass to be recognized by platelet 310 as a body worthy of adherence. Asa result, there is no formation of the above-noted life-threateningembolism 300 associated with aggregation of platelets 310.

Typically, to ensure stability of endothelial cells 220, a patientreceiving stent jacket 100 will be given a platelet aggregation reducingAPI, for example Clopidogrel, for no more than six months, and possiblyless. For example, the patient may receive Clopidogrel for no more thanfor five months, no more than for four months, no more than for threemonths, no more than for two months, or no more than for one month.

At times, the patient receiving stent jacket 100 will not be given aplatelet aggregation reducing API, the unique property of the fiberdiameter, as illustrated in FIG. 32, and the advantage of the apertureminimum center dimension D, alone or in combination, relieving the needfor the platelet aggregation reducing API, altogether. Thus, if thepatient is scheduled to undergo elective surgery during the six-monthadministration, Clopidogrel may be discontinued without substantial fearof platelet aggregation.

Further, if, during a six-month administration period, the recipient ofstent jacket 600 has any reaction, including ulcers, skin rashes,syncope, myelotoxicity, and TTP, Clopidogrel may be immediately ceasedwithout substantial fear of embolism generation.

Further, Clopidogrel administration may be ceased or not initiated inthe face of patient unresponsiveness to Clopidogrel, an antithrombindeficiency, HD, immune depression, low CCR5, acquired hemophilia, AIDS,and HIV.

Experimental Data

Reference is now made to the chart below showing experimental data,which together with the above description, illustrate the invention in anon-limiting fashion.

Optimization of jacket stent fiber thickness and aperture square areareduces the need for an anti coagulation agent, for example Clopidogrel.

Maintaining small total coverage areas provides several additionaladvantages: [0302] 1. crimping the stent for insertion is relativelysimple; [0303] 2. profile of the crimped stent is small; [0304] 3. stentjacket substantially has a minimal influence on the mechanical toproperties of the stent during the delivery and expansion; and [0305] 4.jacket does not require folding during crimping when the coverage areaof the stent is about 9%, or about 10%, or about 11%, or about 12% inself-expanding stent. In general the coverage area is less than 16%.

The chart below provides support that the above-noted parameters ofjacket coverage on a stent can be easily attained in the presentinvention using a fiber diameter of about 12.5 micrometers.

TABLE-US-00002 Stent Fiber Head Apertures Size Covered Size size NeedleAperture Transverse Longitudinal area [mm] [μ] No. No. [μ] [μ] [%] 2.512.5 22 44 166 291 11% 2.75 12.5 22 44 184 291 10% 3 12.5 22 44 202 29110% 3.5 12.5 22 44 237 291  9% 4 12.5 35 70 167 291 11% 4.5 12.5 35 70189 291 10% 5 12.5 35 70 212 291 9& 5.5 12.5 35 70 234 291  9%

It is understood that the phraseology and terminology employed herein isfor descriptive purpose and should not be regarded as limiting.

Unless otherwise defined, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which the invention belongs. In addition, the descriptions,materials, methods, and examples are illustrative only and not intendedto be limiting. Methods and materials similar or equivalent to thosedescribed herein can be used in the practice or testing of the presentinvention.

As used herein, the terms “comprising” and “including” or grammaticalvariants thereof are to be taken as specifying the stated features,integers, steps or components but do not preclude the addition of one ormore additional features, integers, steps, components or groups thereof.This term encompasses the terms “consisting of” and “consistingessentially of”.

As used herein, “a” or “an” mean “at least one” or “one or more”. Theuse of the phrase “one or more” herein does not alter this intendedmeaning of “a” or “an”.

It is expected that during the life of this patent many relevant stentjacket materials will be developed and the scope of the term stentjacket is intended to include all such new technologies a priori.

As used herein the term “about” refers to ±10%.

Additional objects, advantages, and novel features of the presentinvention will become apparent to one ordinarily skilled in the art uponexamination of the following examples, which are not intended to belimiting. Additionally, each of the various embodiments and aspects ofthe present invention as delineated hereinabove and as claimed in theclaims section below finds experimental support in the followingexamples.

It is appreciated that certain features of the invention, which are, forclarity, described in the context of separate embodiments, may also beprovided in combination in a single embodiment. Conversely, variousfeatures of the invention, which are, for brevity, described in thecontext of a single embodiment, may also be provided separately or inany suitable subcombination.

Although the invention has been described in conjunction with specificembodiments thereof, it is evident that many alternatives, modificationsand variations will be apparent to those skilled in the art.Accordingly, it is intended to embrace all such alternatives,modifications and variations that fall within the spirit and broad scopeof the appended claims. All publications, patents and patentapplications mentioned in this specification are herein incorporated intheir entirety by reference into the specification, to the same extentas if each individual publication, patent or patent application wasspecifically and individually indicated to be incorporated herein byreference. In addition, citation or identification of any reference inthis application shall not be construed as an admission that suchreference is available as prior art to the present invention.

1. A stent assembly, comprising: a stent configured to be positioned in a body lumen; and a knitted stent jacket comprising an expansible mesh structure having a coverage area of less than 25%, having approximate aperture diameters greater than 20 micrometers, and surrounding an external surface of the stent and coaxially associated therewith, wherein the stent assembly elutes an amount of an active pharmaceutical agent.
 2. The stent assembly of claim 1, wherein the active pharmaceutical agent is eluted from the stent.
 3. The stent assembly of claim 1, wherein the active pharmaceutical agent is eluted from a coating disposed over a portion of the stent.
 4. The stent assembly of claim 1, wherein the active pharmaceutical agent is time-released according to a predetermined treatment schedule.
 5. The stent assembly of claim 1, wherein the treatment schedule covers a period of 8 hours to a plurality of months.
 6. The stent assembly of claim 1, wherein the active pharmaceutical agent is eluted from the knitted stent jacket.
 7. The stent assembly of claim 1, wherein the active pharmaceutical agent is eluted from a coating on the expansible mesh structure.
 8. The stent assembly of claim 1, wherein the coaxial association comprises the knitted stent jacket being sewed, adhered, glued, folded, or sutured to the stent.
 9. The stent assembly of claim 7, wherein the coaxial association is that the knitted stent jacket is sutured to the stent.
 10. The stent assembly of claim 1, wherein a proximal portion of the knitted stent jacket is attached to a proximal portion of the stent.
 11. The stent assembly of claim 10, wherein a distal portion of the stent jacket is attached to a distal portion of the stent.
 12. The stent assembly of claim 7, wherein the amount of active pharmaceutical agent eluted comprises a therapeutically effective amount.
 13. The stent assembly of claim 1, wherein the active pharmaceutical agent is eluted from the stent, a coating on the stent, the knitted stent jacket, a coating on the knitted stent jacket, or any combination thereof.
 14. (canceled)
 15. The stent assembly of claim 1, wherein the mesh structure is formed from a polymer component comprising one or more poly lactic-co-polyglycolic (“PLGA”), polycaprolactone (“PCL”), polygluconate, polylactic acid-polyethylene oxide, poly(hydroxybutyrate), polyanhydride, poly-phosphoester, poly(amino acids), poly-L-lactide, poly-D-lactide, polyglycolide, or poly(alpha-hydroxy acid) co-polymer(s), polyethylene terephthalate, or any combination thereof.
 16. The stent assembly of claim 13, wherein the mesh structure comprises a single polymer fiber or a plurality of individual polymer fibers.
 17. The stent assembly of claim 13, wherein the polymer is elastic, biocompatible, and hemocompatible.
 18. The stent assembly of claim 1, wherein the knitted stent jacket comprises a mesh of knit fibers each having diameter from approximately 7 to 40 micrometers.
 19. The stent assembly of claim 1, wherein the expansible mesh structure comprises a retracted state and a deployed state, and further wherein the expansible mesh structure defines apertures having a minimum center dimension of 150 micrometers to 200 micrometers in the deployed state.
 20. The stent assembly of claim 1, wherein the expansible mesh structure comprises a retracted state and a deployed state, and further wherein the expansible mesh structure defines apertures having a minimum center dimension of 150 micrometers to 180 micrometers in the deployed state.
 21. (canceled)
 22. The stent assembly of claim 1, wherein the active pharmaceutical agent comprises zolimus, zotarolimus, sirolimus, taxol/paclitaxel, or a combination thereof.
 23. The stent assembly of claim 1, wherein the active pharmaceutical agent comprises an anti-proliferative agent, an antithrombotic agent, an anticoagulant, an antioxidant, a growth factor inhibitor, a collagen inhibitor, a liposome, a steroid or corticosteroid, a statin, endothelial cell seeds, a hydrogel containing endothelial cells, or a combination thereof.
 24. The stent assembly of claim 23, wherein the anti-proliferative agent is present and comprises sirolimus, zolimus or zotarolimus, a taxane, tacrolimus, everolimus, vincritine, viblastine, a HMG-CoA reductase inhibitor, doxorubicin, colchicine, actinomycin D, mitomycin C, cycloporine, mycophenolic acid, triazolopyrimidine, or a combination thereof; wherein the antithrombotic agent is present and comprises heparin, a heparin-like dextran derivative, acid citrate dextrose, coumadin, warfarin, streptokinase, anistreplase, tissue plasminogen activator (tPA), urokinase, abciximab, or a combination thereof; wherein the growth factor inhibitor is present and comprises tranilast, angiopeptin, or a combination thereof; wherein the steroid or corticosteroid is present and comprises cortisone, prednisolone, or both; wherein the statin is present and comprises simvastatin, lovastatin, or a combination thereof; or any combination of the foregoing.
 25. The stent assembly of claim 1, wherein the stent assembly comprises 1 microgram to 200 micrograms of each pharmaceutical agent.
 26. The stent assembly of claim 1, wherein the mesh of the knitted stent jacket comprises 1 microgram to 200 micrograms of each pharmaceutical agent.
 27. (canceled)
 28. The stent assembly of claim 1, wherein the active pharmaceutical agent comprises a limus drug at a concentration of 10 μg/mm² to 80 μg/mm².
 29. The stent assembly of claim 1, wherein the active pharmaceutical agent comprises a limus drug at a concentration of 80 μg/mm² to 140 μg/mm².
 30. (canceled)
 31. The stent assembly of claim 2, wherein the stent comprises a metal alloy coated with a biodegradable polymer, biostable polymer, bioresorbable polymer, or a combination thereof.
 32. The stent assembly of claim 1, wherein the stent comprises a biodegradable material.
 33. The stent assembly of claim 32, wherein the biodegradable material comprises a polymer.
 34. The stent assembly of claim 32, wherein the biodegradable material comprises a metal alloy.
 35. (canceled)
 36. (canceled) 